Prodrugs of excitatory amino acids

ABSTRACT

This invention relates to synthetic excitatory amino acid prodrugs of formula (I) wherein the residues R 11 , R 12  and R 13  are as defined in claim 1. The invention further relates to processes for the preparation of the compounds of formula (I), and to pharmaceutical compositions for the treatment of neurological and psychiatric disorders comprising said compounds.

[0001] This invention relates to synthetic excitatory amino acidprodrugs (and their pharmaceutically acceptable salts) and processes fortheir preparation. The invention further relates to methods of using,and pharmaceutical compositions comprising, the compounds for thetreatment of neurological disorders and psychiatric disorders.

[0002] Treatment of neurological or psychiatric disorders, such asanxiety disorder, have been linked to selective activation ofmetabotropic excitatory amino acid receptors such as(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, also known asLY354740, which is disclosed in U.S. Pat. No. 5,750,566 (the '566patent) issued May 12, 1998 is an active mGluR2 receptor agonist. CNSDrug Reviews, 5, pgs. 1-12 (1999).

[0003] The present invention provides for a prodrug form of LY354740which enhances the oral exposure of LY354740. The present invention alsoprovides for prodrug forms of other compounds which possess improvedoral exposure. Compounds of the present invention represent an improvedapproach for maintaining LY354740-like safety and efficacy in humanswith increased oral bioavailability. Preclinical studies with compoundsof the present invention have shown greatly enhanced oral exposure ofthe parent compound.

[0004] Accordingly, the present invention provides a compound of theformula I

[0005] wherein

[0006] R¹¹ is CO₂R¹⁴ and R¹² is hydrogen or fluoro; or R¹¹ is hydrogenor fluoro and R¹² is CO₂R¹⁴;

[0007] R¹³ and R¹⁴ are, independently, hydrogen, —CHR¹⁵O₂CXR¹⁶ or agroup selected from 3-phthalidyl or

[0008] X is O, N, S, or a bond;

[0009] R¹⁵ is hydrogen, (1-10C) alkyl, (2-4C) alkenyl, aryl, orarylalkyl;

[0010] R¹⁶ is (1-10C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, or aryl;and

[0011] R¹⁷ is hydrogen, (1-10C) alkyl, or phenyl;

[0012] provided when R¹⁴ is hydrogen, R¹³ is not hydrogen;

[0013] or a pharmaceutically acceptable salt thereof.

[0014] Compounds of the present invention have been found to be usefulprodrugs for selective agonists of metabotropic glutamate receptors, andare therefore useful in the treatment of diseases of the central nervoussystem such as neurological diseases, for example neurodegenerativediseases, and as antipsychotic, anxiolytic, drug-withdrawal,antidepressant, anticonvulsant, analgesic and anti-emetic agents.

[0015] It will be appreciated that the compounds of formula (I) containat least four asymmetric carbon atoms, three being in the cyclopropanering and one being at the α-carbon of the amino acid group within thecyclopentane ring. Additional asymmetric carbons may be present in thegeneric radicals as defined. Accordingly, the compounds of the inventionmay exist in and be isolated in enantiomerically pure form, in racemicform, or in a diastereoisomeric mixture.

[0016] The amino acid moiety within the cyclopentane ring preferably hasthe natural amino acid configuration, i.e. the L-configuration relatingto D-glyceraldehyde.

[0017] The present invention includes pharmaceutically acceptable saltsof the compound of formula I. These salts can exist in conjunction withthe acidic or basic portion of the molecule and can exist as acidaddition, primary, secondary, tertiary, or quaternary ammonium, alkalimetal, or alkaline earth metal salts. Generally, the acid addition saltsare prepared by the reaction of an acid with a compound of formula I.The alkali metal and alkaline earth metal salts are generally preparedby the reaction of the hydroxide form of the desired metal salt with acompound of formula I.

[0018] Acids commonly employed to form such salts include inorganicacids, for example hydrochloric, hydrobromic, nitric, sulphuric orphoshoric acids, or with organic acids, such as organic carboxylicacids, for example, glycollic, maleic, hydroxymaleic, fumaric, malic,tartaric, citric, salicyclic, o-acetoxybenzoic, or organic sulphonicacids, such as 2-hydroxyethane sulphonic, toluene-p-sulphonic,methanesulfonic, ethanesulfonic or naphthalene-2-sulphonic acid.

[0019] In addition to pharmaceutically acceptable salts, other salts areincluded in the invention. They may serve as intermediates in thepurification of compounds or in the preparation of other, for examplepharmaceutically-acceptable, acid addition salts, or are useful foridentification, characterization or purification.

[0020] A variety of physiological functions have been shown to besubject to influence by excessive or inappropriate stimulation ofexcitatory amino acid transmission. The formula I compounds of thepresent invention are believed to have the ability to treat a variety ofneurological disorders in mammals associated with this condition,including acute neurological disorder such as cerebral deficitssubsequent to cardiac bypass surgery and grafting, stroke, cerebralischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiacarrest, and hypoglycemic neuronal damage. The formula I compounds arebelieved to have the ability to treat a variety of chronic neurologicaldisorders, such as Alzheimer's disease, Huntington's Chorea, amyotrophiclateral sclerosis, AIDS-induced dementia, ocular damage and retinopathy,cognitive disorders, and idiopathic and drug-induced Parkinson's. Thepresent invention also provides methods for treating these disorderswhich comprises administering to a patient in need thereof an effectiveamount of a compound of formula I or a pharmaceutically acceptable saltthereof.

[0021] The formula I compounds of the present invention treat a varietyof other neurological disorders in mammals that are associated withglutamate dysfunction, including muscular spasms, convulsions, migraineheadaches, urinary incontinence, psychosis, (such as schizophrenia),drug tolerance and withdrawal (such as nicotine, opiates andbenzodiazepines), anxiety and related disorders, emesis, brain edema,chronic pain, and tardive dyskinesia. The formula I compounds are alsouseful as antidepressant and analgesic agents. Therefore, the presentinvention also provides methods for treating these disorders whichcomprise administering to a patient in need thereof an effective amountof the compound of formula I, or a pharmaceutically acceptable saltthereof.

[0022] A compound of formula I may be made by a process which isanalogous to one known in the chemical art for the production ofstructurally analogous heterocyclic compounds or by a novel processdescribed herein. Such processes and intermediates useful for themanufacture of a compound of formula I as defined above are provided asfurther features of the invention and are illustrated by the followingprocedures in which, unless otherwise specified, the meanings of thegeneric radicals are as defined above.

[0023] As shown in Scheme 1 below, compounds of formula I are convertedvia enzymatic or hydrolytic process in vivo, to form compounds offormula III, where R¹³ and R¹⁴ are both hydrogen (a di-acid).

[0024] A variety of physiological functions have been shown to besubject to influence by excessive or inappropriate stimulation ofexcitatory amino acid transmission. The compounds of formula I of thepresent invention are believed to have the ability to treat a variety ofneurological disorders in mammals associated with this condition,including acute neurological disorder such as cerebral deficitssubsequent to cardiac bypass surgery and grafting, stroke, cerebralischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiacarrest, and hypoglycemic neuronal damage. The compounds of formula I arebelieved to have the ability to treat a variety of chronic neurologicaldisorders, such as Alzheimer's disease, Huntington's Chorea, amyotrophiclateral sclerosis, AIDS-induced dementia, ocular damage and retinopathy,cognitive disorders, and idiopathic and drug-induced Parkinson's. Thepresent invention also provides methods for treating these disorderswhich comprises administering to a patient in need thereof an effectiveamount of a compound of formula I or a pharmaceutically acceptable saltthereof.

[0025] The compounds of formula I of the present invention are alsobelieved to have the ability to treat a variety of other neurologicaldisorders in mammals that are associated with glutamate dysfunction,including muscular spasms, convulsions, migraine headaches, urinaryincontinence, psychosis, (such as schizophrenia), drug tolerance andwithdrawal (such as nicotine, opiates and benzodiazepines), anxiety andrelated disorders, emesis, brain edema, chronic pain, and tardivedyskinesia. The compounds of formula I are also useful as antidepressantand analgesic agents. Therefore, the present invention also providesmethods for treating these disorders which comprise administering to apatient in need thereof an effective amount of the compound of formulaI, or a pharmaceutically acceptable salt thereof.

[0026] A compound of formula I may be made by a process which isanalogous to one known in the chemical art for the production ofstructurally analogous heterocyclic compounds or by a novel processdescribed herein. Such processes and intermediates useful for themanufacture of a compound of formula I as defined above are provided asfurther features of the invention and are illustrated by the followingprocedures in which, unless otherwise specified, the meanings of thegeneric radicals are as defined above.

[0027] (A) For a compound of formula I in which R¹³ is an ester and R¹⁴is hydrogen, deprotecting the amine protecting group, R^(m), and thecarboxy protecting group, R¹⁴, of a compound of formula II

[0028] in which R¹³ is an ester, R¹⁴ is a carboxy protecting ester groupas described in General Procedure 2 for Examples 13-18.

[0029] (B) For a compound of formula II in which R¹³ is an ester, R¹⁴ isa carboxy protecting group, esterifying a compound of formula II whereR¹³ is hydrogen and R¹⁴ is a carboxy protecting group as described inGeneral Procedure 1 for Examples 1-6.

[0030] (C) For a compound of formula II in which R¹³ is hydrogen and R¹⁴is not hydrogen, selectively esterifying a compound of formula II inwhich R¹³ and R¹⁴ are both hydrogen (a di-acid) as described in ExamplePreparation 1.

[0031] (D) For a compound of formula II in which R¹³ and R¹⁴ are bothhydrogen (a di-acid), amidating the amine group of a compound of formulaI with an amine protecting group as described in Example Preparations 1Aand 2.

[0032] (E) For a compound of formula I where R¹³ is hydrogen and R¹⁴ isan ester group, deprotecting and ring-opening a compound of formula IV

[0033] as described in Examples 19-26.

[0034] (F) For a compound of formula IV in which R¹⁴ is an ester group,esterifying a compound of formula IV in which R¹⁴ is hydrogen asdescribed in Examples 7-12.

[0035] (G) For a compound of formula IV in which R¹⁴ is hydrogen (anacid), protecting and cyclizing a compound of formula III as describedin Example Preparation 3.

[0036] (H) For a compound of formula I in which-R¹³ and R¹⁴ are nothydrogen (a di-ester), deprotecting the amine group of a compound offormula II as described in General Procedure 5 for Examples 42-56.

[0037] (I) For a compound of formula II in which R¹³ and R¹⁴ are nothydrogen (a di-ester), esterifying the carboxy groups of a compound offormula II in which R¹³ and R¹⁴ are both hydrogen (a di-acid) asdescribed in General Procedure 4 for Examples 27-41.

[0038] The term “amine protecting group”, as used herein, refers tothose groups intended to protect or block the nitrogen group againstundesirable reactions during synthetic procedures. Choice of thesuitable amine protecting group used will depend upon the conditionsthat will be employed in subsequent reaction steps wherein protection isrequired, as is well within the knowledge of one of ordinary skill inthe art. Commonly used amine protecting groups are disclosed in T. W.Greene and P. G. M. Wuts, Protective Groups In Organic Synthesis, 3rdEd. (John Wiley & Sons, New York (1999)). Suitable amine protectinggroups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl,t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl,trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, alpha-chlorobutyryl,benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like;sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like,carbamate forming groups such as benzyloxycarbonyl,p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl, alpha,alpha-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl andthe like; and silyl groups such as trimethylsilyl and the like.Preferred suitable amine protecting groups are formyl, acetyl,methyloxycarbonyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl,benzyl, allyloxycarbonyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl(Cbz).

[0039] The term “carboxy protecting group” as used herein refers to oneof the ester derivatives of the carboxylic acid group commonly employedto block or protect the carboxylic acid group while reactions arecarried out on other functional groups of the compound. Particularvalues of R¹³ and R¹⁴ carboxyl protecting ester groups include, forexample, methyl, ethyl, tert-butyl, benzyl, methoxymethyl,trimethylsilyl, allyl and the like. Further examples of such groups maybe found in T. W. Greene and P. G. M. Wuts, Protecting Groups in OrganicSynthesis, 3^(rd). Ed. (John Wiley & Sons, N.Y. (1999)). The ester isdecomposed by using a conventional procedure which does not affectanother portion of the molecule. For example, protecting group removalof a compound of Formula II in which R¹⁴ is allyl using a metal catalystsuch as tetrakistriphenylphosphine palladium(0) to produce compounds offormula I where R¹¹ is CO₂R¹⁴, R¹² and R¹⁴ are hydrogen, and R¹³ is—CHR¹⁵O₂CXR¹⁶.

[0040] Whereafter, for any of the above procedures, when apharmaceutically acceptable salt of a compound of formula I is required,it is obtained by reacting the acid of formula I with a physiologicallyacceptable base or by reacting a basic compound of formula I with aphysiologically acceptable acid or by any other conventional procedure.

[0041] The term “(1-10C) alkyl” represents a straight, branched, orcyclic alkyl chain having from one to ten carbon atoms. Typical straightor branched (1-10C) alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, heptyl,n-octyl, 2,2-dimethylhexyl, 2,5-dimethylhexyl, 2-methylheptyl,4-methylheptyl, 2,2,4-trimethylpentyl, 2,3,4-trimethylpentyl, nonyl,3,5,5-trimethylhexyl, decyl, 3,7-dimethyloctyl, and the like. The term“(1-10C) alkyl” includes within it the terms “(1-6C) alkyl” and “(1-4C)alkyl”. Typical cyclic alkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and the like. Typical (1-6C) alkylgroups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0042] The term “1(2-4C) alkenyl” represents straight or branchedunsaturated alkyl chains having from two to ten carbon atoms, and havingone or more carbon-carbon double bond, such as, dienes. This group alsoincludes both E and Z isomers. Representative radicals for this groupinclude vinyl, allyl, allenyl, 1-butenyl, 2-butenyl,2-methyl-1-propenyl, 3-butenyl, 2-methyl-2-propenyl, butadienyl, and thelike.

[0043] The term “(2-4C) alkynyl” means an aliphatic hydrocarbon groupcontaining a carbon-carbon triple bond and which may be straight orbranched having about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl or ethyl areattached to a linear alkynyl chain.

[0044] The term “aryl” represents groups such as phenyl, substitutedphenyl, and polycyclic aromatic rings such as 1-naphthyl or 2-naphthyl.

[0045] The term “arylalkyl” represents a (1-4C) alkyl group bearing oneor more aryl groups. Representatives of this latter group includebenzyl, 2-nitrobenzyl, 4-nitrobenzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, 4-phenylbutyl, 2-methyl-2-phenylpropyl,(4-chlorophenyl)methyl, (2,6-dichlorophenyl)-methyl,bis(2,6-dichlorophenyl)methyl, (4-hydroxyphenyl)-methyl,(2,4-dinitrophenyl)methyl, triphenylmethyl,(4-methoxyphenyl)diphenylmethyl, bis(4-methoxyphenyl)methyl,α-naphthyldiphenylmethyl, bis(2-nitrophenyl)methyl, and the like.

[0046] The term “substituted phenyl,” as used herein, represents aphenyl group substituted with one or two moieties chosen from the groupconsisting of halogen, hydroxy, cyano, nitro, (1-10C) alkyl, (1-4C)alkoxy, alkoxycarbonyl, protected carboxy, carboxymethyl, hydroxymethyl,amino, protected amino, aminomethyl, or trifluoromethyl. Examples of asubstituted phenyl group include 4-chlorophenyl, 2,6-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl,4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl,2-fluorophenyl, 4-hydroxyphenyl, 3-hydroxy-phenyl, 2,4-dihydroxyphenyl,3-nitrophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-methylphenyl,4-ethylphenyl, 4-ethoxy-phenyl, 4-carboxyphenyl,4-(hydroxymethyl)phenyl, 4-aminophenyl, 4-propylphenyl, 4-butylphenyl,4-t-butyl-phenyl, 3-fluoro-2-methylphenyl, 2,3-difluorophenyl,2,6-difluorophenyl, 2,6-dimethylphenyl, 2-fluoro-5-methyl-phenyl,2,4,6-trifluorophenyl, 2-trifluoromethylphenyl,2-chloro-5-trifluoromethylphenyl, 2,4-bis(trifluoromethyl)-phenyl,3,5-bis(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3,5-dimethoxyphenyl, 4-hydroxy-3-methyl-phenyl,3,5-dimethyl-4-hydroxyphenyl, 4-hydroxy-3-(hydroxymethyl)phenyl,2-amino-5-methylphenyl, 4-amino-3-trifluoromethylphenyl,3-amino-4-hydroxyphenyl, 2-methyl-4-nitrophenyl,4-methoxy-2-nitrophenyl, 2,4-dinitrophenyl, 3-cyano-4-nitrophenyl, andthe like.

[0047] While all the formula I compounds of the present invention arebelieved to provide prodrug forms of compounds which possess improvedoral exposure, certain compounds of the invention are preferred for suchuse. Preferably, R¹¹ is CO₂R¹⁴; R¹² is hydrogen; R¹³ and R¹⁴ are,independently, 3′-phthalidyl, hydrogen, —CHR¹⁵O₂CXR¹⁶, or R¹⁵ ishydrogen or methyl; R¹⁶ is (1-10C) alkyl or aryl; and X is 0 or a bond.Representative compounds from this preferred group of formula Icompounds include(1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-dibenzoyloxymethyl ester hydrochloride,(1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-dicyclohexyloxycarbonyloxymethyl ester,(1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-di(1′-cyclohexyloxycarbonyloxy-ethyl) ester hydrochloride,(1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]×hexane-2,6-dicarboxylic acid2,6-di-(3′-phthalidyl) ester hydrochloride,(1S,2S,5R,6S)-2-amino-bicyclo[3.10]hexane-2,6-dicarboxylic acid2-isopropyloxycarbonyloxymethyl ester hydrochloride, and(1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid6-tert-butylcarbonyloxymethyl ester.

[0048] Certain compounds of the present invention are more preferred foruse in providing prodrug forms. More preferably, R¹⁵ is hydrogen and Xis a bond. Representative compounds from this more preferred group ofcompounds include(1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dipropanoyloxymethylester hydrochloride,(1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2-(4′-methoxybenzoyloxy)methyl ester hydrochloride, and(1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2-(naphthalene-1′-carbonyloxymethyl) ester hydrochloride.

[0049] Most preferably, the compound of formula (I) is(1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-dipivaloyloxymethyl ester hydrochloride or(1S,2S,5R,6S)-bis-(5-methyl-2-oxo-[1,3]dioxolen-4-ylmethyl)2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylate ethanesulfonic acid or apharmaceutically acceptable salt thereof.

[0050] While all the compounds of formula II of the present inventionare believed to be useful for the synthesis of compounds of formula I,certain compounds are preferred. Preferably, R^(m) istert-butoxycarbonyl and R¹³ and R¹⁴ are H; or R^(m) is allyloxycarbonyl,R¹³ is hydrogen and R¹⁴ is (2-4C) alkenyl group, for example an allylgroup.

[0051] Also useful for the synthesis of compounds of formula I arecompounds where the C-2 amino and carboxy groups are protected in theform of a cyclic ring. Preferably, the cyclic ring is an oxazolidinonethat is spiro fused to the 2-postion ofbicyclo[3.1.0]hexane-6-carboxylic acid, for example a compound offormula IV.

[0052] The compounds of formula II of the present invention aregenerally synthesized from compounds of formula III where R¹³ and R¹⁴are both hydrogen. The compounds of formula III are prepared asdescribed in U.S. Pat. No. 5,750,566 which is incorporated by referencein its entirety.

[0053] Generally, compounds of formula II in which R¹³ is —CHR¹⁵O₂CXR¹⁶may be prepared by directly reacting compounds of formula II where R¹³is hydrogen and R¹⁴ is a carboxy protecting group. Compounds of formulaII in which R¹³ and R¹⁴ are —CHR¹⁵O₂CXR¹⁶ may be prepared by reactingcompounds of formula II where R¹³ and R¹⁴ are both hydrogen.

[0054] More specifically, compounds of formula III are reacted withamine protecting agents such as allyl chloroformate in the presence of asuitable aqueous base such as sodium bicarbonate in a suitable solventsuch as dioxane to produce compounds of formula II. Compounds of formulaII are then reacted with carboxy protecting agents such as allylalcohol, EDCI and HOBt in the presence of a suitable base such astriethylamine in a convenient solvent such as dichloromethane to providecompounds of formula V as shown in scheme 2.

[0055] Compounds of formula VI may be prepared from compounds of formulaV, a carboxlic acid, with a substituted alkyl halide of formulaQCHR¹⁵O₂CXR¹⁶ in which Q is, for example, chlorine or bromine as shownin scheme 3. The reaction is conveniently performed in the presence of abase, such as potassium carbonate and an activating agent, such assodium iodide. Convenient solvents include dimethylformamide.

[0056] Compounds of formula VI are reacted with a metal catalyst such astetrakistriphenylphosphine palladium(0) to produce compounds of formulaI where R¹¹ is CO₂R¹⁴, R¹² and R¹⁴ are hydrogen, and R¹³ is—CHR¹⁵O₂CXR¹⁶. The reaction is performed in the presence of a metalcatalyst regenerating agent such as 1,3-dimethylbarbituric acid in aconvenient solvent such as dichloromethane. The acid addition salts maybe prepared by the reaction of an acid such as hydrogen chloride gaswith a compound of formula I. Convenient solvents include ethyl acetate.

[0057] Generally, compounds of formula II in which R¹³ and R¹⁴ are both—CHR¹⁵O₂CXR¹⁶ may be prepared by reacting compounds of formula II whereR¹³ and R¹⁴ are both hydrogen as shown in scheme 4. More specially,compounds of formula II may be prepared by reacting compounds of formulaIII with amine protecting agents such as di-tert-butyl dicarbonate inthe presence of a suitable aqueous base such as sodium hydroxide in asuitable solvent such as dioxane to produce compounds of formula IIwhere R_(m) is tert-butyloxycarbonyl.

[0058] Compounds of formula VII may be prepared from compounds offormula II, a dicarboxlic acid, with a substituted alkyl halide offormula QCHR¹⁵O₂CXR¹⁶ in which Q is a suitable leaving group such aschlorine. The reaction is conveniently performed in the presence of abase, such as potassium carbonate and an activating agent, such assodium iodide. Convenient solvents include dimethylformamide.

[0059] Compounds of formula VII are reacted with amine deprotectingagents such as an acid to provide compounds of formula I in which R¹¹ isCO₂R¹⁴, R¹³ and R¹⁴ are both —CHR¹⁵O₂CXR¹⁶ or5-methyl-2-oxo-[1,3]dioxolen-4-ylmethyl and R¹² is hydrogen. Convenientacids include trifluoroacetic acid or hydrogen chloride gas saturated ina convenient solvent such as ethyl acetate. Such conditions may producethe corresponding acid salt of the compound of formula I as an amorphousor, directly, a crystalline solid. In the case of an amorphous solid,subsequent crystallization may occur from suitable solvents. In the caseof a crystalline solid formed under reaction conditions, filtration ofthe reaction mixture may afford the crystalline salt directly. Thezwitterionic compound of formula I may be prepared by treatment of theacid salt of formula I with a suitable reagent such as a base, forexample aqueous sodium bicarbonate, or propylene oxide. Additional acidsalts may be prepared by treating the zwitterionic compound of formula Iwith a suitable acid. Suitable acids include ethanesulfonic acid in aconvenient solvent such as methylene chloride.

[0060] Generally, compounds of formula I in which R¹³ is hydrogen andR¹⁴ is —CHR¹⁵O₂CXR¹⁶ may be prepared by reacting compounds of formula IVwhere R¹⁴ is hydrogen as shown in scheme 5. More specially, compounds offormula IV may be prepared by reacting compounds of formula II whereR_(m) is an amine protecting group such as allyloxycarbonyl with analdehyde such as paraformaldehyde in the presence of a suitable acidcatalyst such as p-toluene sulphonic acid. The reaction may be carriedout in a suitable solvent such as benzene with convenient removal ofwater such as azeotropic distillation.

[0061] Compounds of formula IIX may be prepared from compounds offormula IV where R¹⁴ is hydrogen with a substituted alkyl halide offormula QCHR¹⁵O₂CXR¹⁶ in which Q is a suitable leaving group such aschlorine. The reaction is conveniently performed in the presence of abase, such as potassium carbonate. An activating agent, such as sodiumiodide may be added to facilitate the reaction. Convenient solventsinclude dimethylformamide.

[0062] Compounds of formula IIX are reacted with a metal catalyst suchas tetrakistriphenylphosphine palladium(0) to produce compounds offormula I where R¹¹ is CO₂R¹⁴, R¹² and R¹³ are hydrogen, and R¹⁴ is—CHR¹⁵O₂CXR¹⁶. The reaction is conveniently performed in the presence ofa metal catalyst regenerating agent such as 1,3-dimethylbarbituric acidin a suitable solvent such as dichloromethane. The acid addition saltsmay be prepared by the reaction of an acid such as hydrogen chloride gaswith a compound of formula I. Convenient solvents include ethyl acetate.The zwitterionic compound of formula I may be prepared by treatment ofthe acid salt of formula I with a suitable acid scavenger such aspropylene oxide in a suitable solvent such as methanol.

[0063] The term “affecting” refers to a formula I compound acting as anagonist at an excitatory amino acid receptor. The term “excitatory aminoacid receptor” refers to a metabotropic glutamate receptor, a receptorthat is coupled to cellular effectors via GTP-binding proteins. The term“cAMP-linked metabotropic glutamate receptor” refers to a metabotropicreceptor that is coupled to inhibition of adenylate cyclase activity.

[0064] The term “neurological disorder” refers to both acute and chronicneurodegenerative conditions, including cerebral deficits subsequent tocardiac bypass surgery and grafting, cerebral ischemia (for examplestroke resulting from cardiac arrest), spinal cord trauma, head trauma,Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral sclerosis,AIDS-induced dementia, perinatal hypoxia, hypoglycemic neuronal damage,ocular damage and retinopathy, cognitive disorders, idiopathic anddrug-induced Parkinson's Disease. This term also includes otherneurological conditions that are caused by glutamate dysfunction,including muscular spasms, migraine headaches, urinary incontinence,drug tolerance, withdrawal, and cessation (i.e. opiates,benzodiazepines, nicotine, cocaine, or ethanol), smoking cessation,emesis, brain edema, chronic pain, sleep disorders, convulsions,Tourette's syndrome, attention deficit disorder, and tardive dyskinesia.

[0065] The term “psychiatric disorder” refers to both acute and chronicpsychiatric conditions, including schizophrenia, anxiety and relateddisorders (e.g. panic attack and stress-related cardiovasculardisorders), depression, bipolar disorders, psychosis, and obsessivecompulsive disorders.

[0066] If not commercially available, the necessary starting materialsfor the above procedures may be made by procedures which are selectedfrom standard techniques of organic and heterocyclic chemistry,techniques which analogous to the syntheses of known, structurallysimilar compounds, and the procedures described in the Examples,including novel procedures.

[0067] As used herein the term “effective amount” refers to the amountor dose of the compound, upon single or multiple dose administration tothe patient, which provides the desired effect in the patient underdiagnosis or treatment.

[0068] An effective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount or dose of compound administered, anumber of factors are considered by the attending diagnostician,including, but not limited to: the species of mammal; its size, age, andgeneral health; the specific disease involved; the degree of orinvolvement or the severity of the disease; the response of theindividual patient; the particular compound administered; the mode ofadministration; the bioavailability characteristics of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances. For example, a typicaldaily dose may contain from about 25 mg to about 300 mg of the activeingredient. The compounds can be administered by a variety of routesincluding oral, rectal, transdermal, subcutaneous, intravenous,intramuscular, bucal or intranasal routes. Alternatively, the compoundmay be administered by continuous infusion.

[0069] As used herein the term “patient” refers to a mammal, such as amouse, guinea pig, rat, dog or human. It is understood that thepreferred patient is a human.

[0070] The term “treating” (or “treat”) as used herein includes itsgenerally accepted meaning which encompasses prohibiting, preventing,restraining, and slowing, stopping, or reversing progression of aresultant symptom. As such, the methods of this invention encompass boththerapeutic and prophylactic administration.

[0071] The ability of compounds to modulate metabotropic glutamatereceptor function may be demonstrated by examining their ability toinfluence either cAMP production (mGluR 2, 3, 4, 6, 7 or 8) orphosphoinositide hydrolysis (mGluR 1 or 5) in cells expressing theseindividual human metabotropic glutamate receptor (mGluR) subtypes. (D.D. Schoepp, et al., Neuropharmacol., 1996, 35, 1661-1672 and 1997, 36,1-11).

[0072] The abililty of formula I compounds to treat anxiety or a relateddisorder may be demonstrated using the well known fear potentiatedstartle and elevated plus maze models of anxiety described respectivelyin Davis, Psychopharmacology, 62:1; 1979 and Lister, Psychopharmacol,92: 180-185; 1987.

In Vivo Exposure as Measured by Rat Plasma Concentration

[0073] To study the in vivo exposure of LY354740 following oral dosingof compounds of the present invention in comparison to LY354740, studiesmeasuring the plasma concentrations of LY354740 in rats were performed.

[0074] Mature Fischer 344 male rats (190-270 gram) were obtained fromHarlan Sprague-Dawley, Cumberland, Ind., USA and acclimated in the studyhousing for 3 days. On day 4, test compounds were dissolved in bufferedwater (1 mg/ml=test compound/20 mM potassium dihydrogen phosphate, pH=2)and given orally as a single 5 mg/kg dose. Blood samples were collectedthrough orbital sinus or cardiac puncture (last time point) at 0.5 and 1hour or, alternatively, 1 and 3 hours. Plasma samples were stored at−20° C. in the presence of phenylmethylsulfonyl fluoride, a proteaseinhibitor, prior to analysis. Plasma samples and internal standardcompounds were pretreated by solid phase extraction (SAX support,methanol/water/dilute acetic acid). As shown in the second row of Table1, below, the plasma concentrations (ng/ml) of LY354740 for each testcompound were determined by LC/MS/MS and are presented as a sum of theconcentrations at the 0.5 and 1 hour or, alternatively, 1 and 3 hoursample time points. TABLE 1 Comparison of plasma concentrations ofLY354740 and compounds of the present invention Plasma Concentration ofCompound LY354740, ng/ml (@ 5 mg/kg p. o.) (sum of 0.5 and 1 hour)LY354740 466 Example 14 1494 Example 15 3600 Example 17 2403 Example 211545 Example 42 3898 Example 43 1831 Example 47 3225 Example 50 2197Example 53 1450 Example 54 1354 Example 57 4786

[0075] The compounds of the present invention are preferably formulatedprior to administration. Therefore, another aspect of the presentinvention is a pharmaceutical formulation comprising a compound offormula I a pharmaceutically acceptable metabolically labile esterthereof, or a pharmaceutically acceptable salt thereof, and apharmaceutically-acceptable carrier, diluent, or excipient. The presentpharmaceutical formulations are prepared by known procedures usingwell-known and readily available ingredients. In making the compositionsof the present invention, the active ingredient will usually be mixedwith a carrier, or diluted by a carrier, or enclosed within a carrier,and may be in the form of a capsule, sachet, paper, or other container.When the carrier serves as a diluent, it may be a solid, semi-solid, orliquid material which acts as a vehicle, excipient, or medium for theactive ingredient. The compositions can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, suspensions,emulsions, solutions, syrups, aerosols, ointments containing, forexample, up to 10% by weight of active compound, soft and hard gelatincapsules, suppositories, sterile injectable solutions, and sterilepackaged powders.

[0076] Some examples of suitable carriers, excipients, and diluentsinclude lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum,acacia, calcium phosphate, alginates, tragacanth, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose,water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc,magnesium stearate, and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents, or flavoring agents.Compositions of the invention may be formulated so as to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart.

[0077] The compositions are preferably formulated in a unit dosage form,each dosage containing from about 5 mg to about 500 mg, more preferablyabout 25 mg to about 300 mg of the active ingredient. The term “unitdosage form” refers to a physically discrete unit suitable as unitarydosages for human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical carrier, diluent, or excipient.

[0078] The following Examples further illustrate the compounds of thepresent invention and the methods for their synthesis. The Examples arenot intended to be limiting to the scope of the invention in anyrespect, and should not be so construed. All experiments were run undera positive pressure of dry nitrogen or argon. All solvents and reagentswere purchased from commercial sources and used as received, unlessotherwise indicated. Dry tetrahydrofuran (THF) was obtained bydistillation from sodium or sodium benzophenone ketyl prior to use.Proton nuclear magnetic resonance (¹H NMR) spectra were obtained on a GEQE-300 spectrometer at 300.15 MHz, a Bruker AM-500 spectrometer at 500MHz, a Bruker AC-200P spectrometer at 200 MHz or a Varian Inova at 500MHz. Free atom bombardment mass spectroscopy (FABMS) was performed on aVG ZAB-2SE instrument. Field desorption mass spectroscopy (FDMS) wasperformed using either a VG 70SE or a Varian MAT 731 instrument. Opticalrotations were measured with a Perkin-Elmer 241 polarimeter.Chromatographic separation on a Waters Prep 500 LC was generally carriedout using a linear gradient of the solvents indicated in the text. Thereactions were generally monitored for completion using thin layerchromatography (TLC). Thin layer chromatography was performed using E.Merck Kieselgel 60 F₂₅₄ plates, 5 cm×10 cm, 0.25 mm thickness. Spotswere detected using a combination of UV and chemical detection (platesdipped in a ceric ammonium molybdate solution [75 g of ammoniummolybdate and 4 g of cerium (IV) sulfate in 500 mL of 10% aqueoussulfuric acid] and then heated on a hot plate). Flash or silica gelchromatography was performed as described by Still, et al. Still, Kahn,and Mitra, J. Org. Chem., 43, 2923 (1978). Elemental analyses forcarbon, hydrogen, and nitrogen were determined on a Control EquipmentCorporation 440 Elemental Analyzer, or were performed by the UniversidadComplutense Analytical Centre (Facultad de Farmacia, Madrid, Spain).Melting points were determined in open glass capillaries on a Gallenkamphot air bath melting point apparatus or a Büchi melting point apparatus,and are uncorrected. The number in parenthesis after the compound namerefers to the compound number.

[0079] The abbreviations, symbols and terms used in the examples havethe following meanings.

[0080] Ac=acetyl

[0081] Anal.=elemental analysis

[0082] Bn or Bzl=benzyl

[0083] Bu=butyl

[0084] BOC=tert-butoxycarbonyl

[0085] calcd=calculated

[0086] D₂O=deuterium oxide

[0087] DCC=dicyclohexylcarbodiimide

[0088] DIBAL-H=diisobutyl aluminum hydride

[0089] DMAP=dimethylaminopyridine

[0090] DMF=dimethylformamide

[0091] DMSO=dimethylsulfoxide

[0092] EDCI=N-ethyl-N′N′-dimethylaminopropyl carbodiimide

[0093] Et=ethyl

[0094] EtOAc=ethyl acetate

[0095] EtOH=ethanol

[0096] FAB=Fast Atom Bombardment (Mass Spectrascopy)

[0097] FDMS=field desorption mass spectrum

[0098] HOAt=1-hydroxy-7-azabenzotriazole

[0099] HOBt=1-hydroxybenzotriazole

[0100] HPLC=High Performance Liquid Chromatography

[0101] HRMS=high resolution mass spectrum

[0102] i-PrOH=isopropanol

[0103] IR=Infrared Spectrum

[0104] L=liter

[0105] Me=methyl

[0106] MeOH=methanol

[0107] MPLC=Medium Pressure Liquid Chromatography

[0108] Mp=melting point

[0109] MTBE=t-butyl methyl ether

[0110] NBS=N-bromosuccinimide

[0111] NMDBA=1,3-dimethylbarbituric acid

[0112] NMR=Nuclear Magnetic Resonance

[0113] Ph=phenyl

[0114] p.o.=oral administration

[0115] i-Pr=isopropyl

[0116] Rochelle's Salt=potassium sodium tartrate

[0117] SM=starting material

[0118] TBS=tert-butyldimethylsilyl

[0119] TEA=triethylamine

[0120] Temp.=temperature

[0121] TFA=trifluoroacetic acid

[0122] THF=tetrahydrofuran

[0123] TLC=thin layer chromatography

[0124] t-BOC=tert-butoxycarbonyl

Example Preparation 1

[0125] Synthesis of(1S,2S,5R,6S)-2-allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 6-allyl ester

[0126] A.(1S,2S,5R,6S)-2-Allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid

[0127] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid(15.0 g, 73.9 mmol) was slowly dissolved in 250 mL of NaHCO₃ sat. (250mL). After complete solution, dioxane (100 mL) and allyl chloroformate(15.7 mL, 147.8 mmol) were added at room temperature and the mixture wasstirred overnight. The reaction mixture was diluted with water (100 mL)and washed with ethyl acetate (3×). The organic layer was extracted oncewith sat. NaHCO₃. The combined aqueous layers were acidified to pH 1with 4N HCl and extracted with ethyl acetate (2×). The organic layer wasdried over magnesium sulfate, filtered and concentrated to provide anoil (13.4 g, 67% yield) that was used without further purification.

[0128]¹H-NMR (CD₃OD) δ: 6.01-5.82 (m, 1H); 5.35-5.13 (m, 2H); 4.51 (d,J=5.1 Hz, 2H); 2.48-1.78 (m, 5H); 1.69-1.62 (m, 1H); 1.45-1.29 (m, 1H).¹³C-NMR (CD₃OD) δ: 176.7, 176.6, 158.3, 134.2, 117.4, 67.3, 66.3, 35.8,33.1, 29.9, 27.0, 22.0.

[0129] B.(1S,2S,5R,6S)-2-Allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 6-allyl ester

[0130] To a suspension of(1S,2S,5R,6S)-2-allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid (13.4 g, 49.8 mmol) in dichloromethane (400 mL),N-ethyl-N′-dimethylaminopropylcarbodiimide (9.55 g, 49.8 mmol) anddimethylaminopyridine (0.61 g, 5.0 mmol) were added at room temperatureunder nitrogen. Allyl alcohol (3.4 mL, 49.8 mmol) was added and themixture was stirred overnight at room temperature. The reaction mixturewas diluted with dichloromethane and washed with water (2×). The organiclayer was dried over magnesium sulfate, filtered and concentrated toprovide the title compound (6.8 g, 44% yield) as an oil.

[0131]¹H-NMR (CD₃OD) δ: 6.01-5.82 (m, 1H); 5.35-5.13 (m, 2H); 4.51 (d,J=5.1 Hz, 2H); 2.48-1.78 (m, 5H); 1.69-1.62 (m, 1H); 1.45-1.29 (m, 1H).

Example Preparation 2

[0132] Synthesis of(1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid

[0133] A 1 L flask was charged with(1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acidmonohydrate (24.4 g, 0.12 mol, 1 equiv), dioxane (200 mL) anddi-tert-butyl dicarbonate (52.4 g, 0.24 mol, 2.0 equiv). The suspensionwas vigorously stirred while sodium hydroxide 1N (420 mL, 3.5 equiv) wasadded. The mixture was stirred for 2 days, then 2.0 more equiv ofdi-tert-butyl dicarbonate were added and the reaction stirred for 3additional days at rt. After 5 total days of reaction, water (400 mL)was added to dissolve the salts. The aqueous layer was extracted withethyl acetate (4×100 mL) to remove the excess of reagent, and then takento ca. pH=2 using 6 N hydrochloric acid. The acidic aqueous phase wasthen extracted using ethyl ether (6×200 mL). The combined organic layerswere washed with water (250 mL) and brine (250 mL). After drying oversodium sulfate, solvents were evaporated under vacuum to afford a foamywhite solid (26.4 g). 77% Yield. mp 100-101° C.

[0134] [α]_(D) ²⁵=−41.1° (c=1.0, MeOH).

[0135]¹H NMR (Methanol-d₄) δ: 4.98 (brs, 1H), 2.44 (dd, 1H, J=6.2, 2.6Hz), 2.19-1.92 (m, 4H), 1.62 (t, 1H, J=2.8 Hz), 1.43 (s, 9H), 1.29 (m,1H).

[0136]³C NMR (Methanol-d₄) δ: 175.6, 175.2, 158.2, 60.1, 34.6, 31.9,28.4, 27.2, 25.6, 20.6.

[0137] MS (Neg. Electrospray): 284.2 (M⁺−H).

Example Preparation 3

[0138] Synthesis of(1′S,2′S,5′R,6′S)-3-Allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylicacid

[0139](1S,2S,5R,6S)-2-Allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid, Example A.1, (19.17 g, 64.33 mmol), paraformaldehyde (7.73 g,257.32 mmol) and p-toluenesulphonic acid (0.612 g, 3.216 mmol) wereslurried in 200 mL of benzene and refluxed with azeotropic removal ofwater for two hours. The mixture was cooled to room temperature anddiluted with 200 mL of ethyl acetate, washed twice with brine and driedover MgSO₄. Concentration afforded a slighly hygroscopic solid (17.6 g,97%) >95% pure by NMR.

[0140]¹H-NMR (CDCl₃, 200.15 MHz): 6.10-5.90 (m, 1H); 5.41-5.21 (m, 4H);4.65 (dt, J=5.6, 1.3 Hz, 2H); 2.51-2.49 (m, 1H); 2.33-2.18 (m, 2H);2.04-1.92 (m, 3H); 1.75-1.70 (m, 1H). ¹³C-NMR (CD₃OD, 50 MHz): 176.1,175.4, 153.0, 133.5, 118.9, 78.4, 67.8, 67.4, 33.1, 27.2 (×2), 26.0,23.9.

General Procedure 1

[0141] General Procedure for Esterification of(1S,2S,5R,6S)-2-Allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 6-allyl ester or(1′S,2′S,5′R,6′S)-3-Allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylicacid

[0142](1S,2S,5R,6S)-2-Allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 6-allyl ester (Example Preparation 1) (1.0 equiv) or(1′S,2′S,5′R,6′S)-3-allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylicacid (Example Preparation 3) (1.0 equiv) was dissolved in drydimethylformamide (0.5 M solution) under nitrogen and potassiumcarbonate or cesium carbonate (1.0 equiv) was added at room temperatureor 0° C. After 5 min, the corresponding halide (1.0 equiv) and sodiumiodide (1.0 equiv) were added. The reaction mixture was stirred at roomtemperature overnight. Water was added and the aqueous phase wasextracted with two portions of ethyl acetate. The combined organic phasewas washed with cold water, dried over magnesium sulfate andconcentrated to dryness. The crude mixture was purified by silica gelflash-chromatography using the appropriate eluent (typically mixtures ofhexanes/ethyl acetate).

EXAMPLE 1

[0143](1S,2S,5R,6S)-2-Allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 6-allyl ester 2-(3′-phthalidyl) ester

[0144] The title compound was prepared according to General Procedure 1using 3-bromophthalide (which was obtained from phthalide as describedby Koten et al. Org. Synth. Coll. Vol. V, 145-147).

[0145] 92% Yield. Foamy white solid. Mixture of diastereomers.

[0146]¹H NMR (CDCl₃) δ (Mixture of diastereomers): 7.94-7.91 (m,1H),7.78-7.56 (m, 3H), 7.42 (brs, 1H), 5.96-5.78 (m, 2H), 5.60 (brs,1H), 5.34-5.15 (m, 4H), 4.56-4.51 (m, 4H), 2.61-2.54 (m, 1H), 2.44-2.34(m, 1H), 2.22-1.94 (m, 3H), 1.79-1.72 (m, 1H), 1.39-1.21 (m, 1H).

[0147]¹³C NMR (CDCl₃) δ (Mixture of diastereomers): 171.6, 171.4, 171.1,167.6, 155.5, 144.1, 134.8, 132.2, 131.9, 131.8, 131.2, 126.3, 125.6,123.7, 118.5, 118.4, 117.9, 93.3, 66.7, 66.6, 65.8, 65.5, 65.4, 34.0,32.3, 28.4, 28.0, 26.7, 26.0, 21.2, 21.0.

[0148] MS (Electrospray): 464.2 (M⁺+Na).

EXAMPLE 2

[0149] (1S,2S,5R,6S)-2-Allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-allyl ester2-isopropyloxycarbonyloxymethyl ester

[0150] The title compound was prepared according to General Procedure 1using chloromethyl isopropyl carbonate (which was obtained fromchloromethyl chloroformate as described by Patonay, T. et al, Synth.Commun. 1990, 20, 2865-2885 and Davidsen et al. J. Med. Chem. 1994, 37,4423-4429).

[0151] 69% Yield. Colorless syrup.

[0152] [α]_(D) ²⁵=−6.36° (c=0.66, CHCl₃).

[0153]¹H NMR (CDCl₃) δ: 5.92-5.77 (m, 2H), 5.89 (brs, 1H), 5.80 (brs,2H), 5.35-5.17 (m, 4H), 4.91 (m, 1H), 4.54 (m, 4H), 2.45-2.37 (m, 2H),2.10-1.95 (m, 3H), 1.78 (t, 1H, J=2.6 Hz), 1.33-1.26 (m, 1H), 1.31 (d,6H, J=6.4 Hz).

[0154]¹³C NMR (CDCl₃) δ: 171.6, 171.1, 155.4, 153.0, 132.3, 131.8,118.1; 117.5, 82.4, 72.8, 66.3, 65.5, 65.1, 34.1, 32.0, 28.2, 26.3,21.4, 21.3, 20.9.

[0155] MS (Electrospray): 425.8 (M⁺+Na).

EXAMPLE 3

[0156](1S,2S,5R,6S)-2-Allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 6-allyl ester 2-(4′-methoxy-benzoyloxymethyl) ester

[0157] The title compound was prepared according to General Procedure 1using chloromethyl p-methoxybenzoate (which was readily obtained asdescribed by Davidsen et al. J. Med. Chem. 1994, 37, 4423-4429).

[0158] 52% Yield.

[0159]¹H-NMR (CDCl₃): 7.99 (d, J=9.1 Hz, 2H), 6.90 (d, J=9.1 Hz, 2H),6.00 (s, 2H), 5.93-5.70 (m, 2H), 5.56 (s, 1H), 5.31-5.09 (m, 4H), 4.51(d, J=5.6 Hz, 2H), 4.42 (d, J=5.6 Hz, 2H), 3.83 (s, 3H), 2.49-2.38 (m,2H), 2.16-1.71 (m, 4H), 1.34-1.18 (m, 1H).

EXAMPLE 4

[0160](1S,2S,5R,6S)-2-Allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 6-allyl ester 2-(naphthalene-2′-carbonyloxymethyl) ester

[0161] The title compound was prepared according to General Procedure 1using chloromethyl 2-napthtoate (which was obtained using a similarprocedure to the one described by Davidsen et al. J. Med. Chem. 1994,37, 4423-4429).

[0162] 63% yield. Oil.

[0163] IR (KBr) ν: 3360, 3059, 2988, 2939, 2876, 1732, 1653, 1508, 1458,1417, 1329, 1283, 1258, 1178, 1156, 981 cm⁻¹.

[0164]¹H NMR (CDCl₃) δ: 8.66 (m, 1H), 8.07 (m, 1H), 7.95 (m, 1H), 7.88(m, 2H), 7.66-7.51 (m, 2H), 6.13 (s, 2H), 5.98-5.72 (m, 2H), 5.48 (brs,1H), 5.18 (m, 4H), 4.54 (m, 2H), 4.44 (m, 2H), 2.56-2.46 (m, 2H),2.27-1.91 (m, 3H), 1.76 (t, 1H, J=3.0 Hz), 1.30 (m, 1H).

[0165]¹³C NMR (CDCl₃) δ: 171.6, 171.5, 165.3, 155.5, 135.9, 131.9,129.5, 128.6, 128.3, 127.8, 126.8, 126.0, 125.2, 132.4, 132.3, 118.5,117.8, 80.4, 66.7, 65.8, 65.4, 34.3, 32.4, 28.3, 26.6, 21.2.

[0166] MS (Electrospray): 516.1 (M⁺+Na), 494.1 (M⁺+H).

EXAMPLE 5

[0167](1S,2S,5R,6S)-2-Allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 6-allyl ester 2-(naphthalene-1′-carbonyloxymethyl) ester

[0168] The title compound was prepared according to General Procedure 1using chloromethyl 1-napthtoate (which was obtained using a similarprocedure to the one described by Davidsen et al. J. Med. Chem. 1994,37, 4423-4429).

[0169] 78% yield. Oil.

[0170] IR (KBr) ν: 3366, 3080, 3051, 2991, 2945, 2874, 1732, 1630, 1508,1458, 1417, 1329, 1280, 1248, 1179, 1159, 1119, 987 cm⁻¹.

[0171] 1H NMR (CDCl₃) δ: 8.95 (m, 1H), 8.29 (m, 1H), 8.06 (m, 1H), 7.89(m, 1H), 7.68-7.47 (m, 3H), 6.15 (s, 2H), 5.99-5.69 (m, 2H), 5.51 (brs,1H), 5.20 (m, 4H), 4.54 (m, 2H), 4.43 (m, 2H), 2.57-2.45 (m, 2H),2.28-1.92 (m, 3H), 1.77 (t, 1H, J=3.0 Hz), 1.30 (m, 1H).

[0172]¹³C NMR (CDCl₃) δ: 171.6, 171.5, 165.6, 155.5, 134.3, 133.8,131.5, 131.4, 128.6, 128.1, 126.3, 125.6, 125.2, 124.5, 132.3, 131.9,118.5, 117.8, 80.3, 66.7, 65.8, 65.4, 34.4, 32.4, 28.3, 26.6, 21.2.

[0173] MS (Electrospray): 516.1 (M⁺+Na), 494.1 (M⁺+H).

EXAMPLE 6

[0174](1S,2S,5R,6S)-2-Allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 6-allyl ester 2-cyclohexyloxycarbonyloxymethyl ester

[0175] The title compound was prepared according to General Procedure 1using chloromethyl cyclohexyl carbonate (which was obtained fromchloromethyl chloroformate as described by Patonay, T. et al, Synth.Commun. 1990, 20, 2865-2885 and Davidsen et al. J. Med. Chem. 1994, 37,4423-4429).

[0176] 65% yield. Oil.

[0177] IR (KBr) ν: 3358, 2941, 2863, 1761, 1728, 1518, 1452, 1415, 1323,1278, 1261, 1155 cm⁻¹.

[0178]¹H NMR (CDCl₃) δ: 5.88 (m, 2H), 5.80 (s, 2H), 5.45 (brs, 1H), 5.25(m, 4H), 4.66 (m, 1H), 4.53 (m, 4H), 2.53-2.40 (m, 2H), 2.24-1.88 (m,5H), 1.81-1.70 (m, 3H), 1.60-1.20 (m, 7H).

[0179]¹³C NMR (CDCl₃) δ: 171.6, 171.2, 155.5, 153.2, 132.4, 132.0,118.5, 117.9, 82.6, 77.8, 66.6, 65.9, 65.5, 34.4, 32.4, 31.3, 28.3,26.6, 25.1, 23.5, 21.2.

[0180] MS (Electrospray): 488.1 (M⁺+Na), 466.2 (M⁺+H).

EXAMPLE 7

[0181] Synthesis of(1′S,2′S,5′R,6′S)-3-Allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylicacid 6′-tert-butylcarbonyloxymethyl ester

[0182] The title compound was prepared according to General Procedure 1using chloromethyl pivalate.

[0183] 67% Yield. Colorless syrup.

[0184] [α]_(D) ²⁵=+47.0° (c=1.52, CHCl₃).

[0185]¹H NMR (CDCl₃) δ: 5.94 (m, 1H), 5.72 (AB system, 2H), 5.38-5.25(m, 2H), 5.34 (brs, 2H), 4.64 (brd, 2H, J=5.9 Hz), 2.58 (brs, 1H), 2.31(m, 2H), 2.05-1.98 (m, 3H), 1.74 (m, 1H), 1.21 (s, 9H),

[0186]¹³C NMR (CDCl₃) δ: 176.5, 173.0, 170.7, 151.1, 131.6, 118.7, 79.3,76.7, 66.1, 66.0, 38.3, 32.0, 26.5, 26.4, 26.1, 24.7, 22.4.

[0187] MS (Electrospray): 396.2 (M⁺+H).

EXAMPLE 8

[0188] Synthesis of(1′S,2′S,5′R,6′S)-3-Allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylicacid 6′-benzoyloxymethyl ester.

[0189] The title compound was prepared according to General Procedure 1using chloromethyl benzoate (which was obtained as described by Davidsenet al. J. Med. Chem. 1994, 37, 4423-4429).

[0190] 66% Yield. Colorless syrup.

[0191] [α]_(D) ²⁵=+32.3° (c=1.5, CHCl₃).

[0192]¹H NMR (CDCl₃) δ: 8.02 (dd, 2H, J=8.8, 0.6 Hz), 7.59-7.52 (m, 1H),7.40 (m, 2H), 5.98-5.79 (m, 1H), 5.97 (brs, 2H), 5.28 (brs, 2H), 5.25(dd, 1H, J=17.0, 1.4 Hz), 5.19 (dd, 1H, J=10.4, 1.4 Hz), 4.57 (ABsystem, 2H), 2.58 (m, 1H), 2.35-2.18 (m, 2H), 2.10-1.92 (m, 3H),1.73-1.62 (m, 1H).

[0193]¹³C NMR (CDCl₃) δ: 173.2, 171.0, 151.2, 133.5, 131.6, 129.8,129.8, 128.8, 128.4, 128.3, 118.9, 79.6, 76.9, 66.4, 66.2, 32.4, 26.8,26.3, 24.8, 22.6.

[0194] MS (Electrospray): 438.2 (M⁺+Na).

EXAMPLE 9

[0195] Synthesis of(1′S,2′S,5′R,6′S)-3-Allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylicacid 6′-isopropoxycarbonyloxymethyl ester.

[0196] The title compound was prepared according to General Procedure 1using chloromethyl isopropyl carbonate (which was obtained fromchloromethyl chloroformate as described by Patonay, T. et al, Synth.Commun. 1990, 20, 2865-2885 and Davidsen et al. J. Med. Chem. 1994, 37,4423-4429).

[0197] 64% Yield. Colorless syrup.

[0198] [α]_(D) ²⁵=+38.2 (c=1.1, CHCl₃).

[0199]¹H NMR (CDCl₃) δ: 5.94-5.80 (m, 1H), 5.63 (AB system, 2H), 5.26(dd, 1H, J=15.6, 1.4 Hz), 5.25 (brs, 2H), 5.18 (dt, 1H, J=8.8, 1.2 Hz),4.82 (m, 1H), 4.55 (m, 2H), 2.50 (m, 1H), 2.30-2.15 (m, 2H), 2.02-1.88(m, 3H), 1.65 (m, 1H), 1.22 (d, 6H, J=6.2 Hz).

[0200]¹³C NMR (CDCl₃) δ: 173.1, 170.7, 153.0, 151.1, 131.6, 118.8, 81.6,76.8, 72.7, 66.3, 66.1, 32.3, 26.8, 26.1, 24.8, 22.4, 21.3, 21.3.

EXAMPLE 10

[0201] Synthesis of(1′S,2′S,5′R,6′S)-3-Allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylicacid 6′-n-butyryloxymethyl ester.

[0202] The title compound was prepared according to General Procedure 1using chloromethyl n-butyrate.

[0203] 51% Yield. Colorless syrup.

[0204] [α]_(D) ²⁵=+44.4° (c=2.0, CHCl₃).

[0205]¹H NMR (CDCl₃) δ: 5.92 (m, 1H), 5.72 (AB system, 2H), 5.37-5.25(m, 2H), 5.33 (brs, 2H), 4.62 (brd, 2H, J=6.0 Hz), 2.58 (brs, 1H),2.37-2.31 (m, 4H), 2.10-1.97 (m, 3H), 1.73-1.56 (m, 3H), 0.94 (t, 3H,J=8.0 Hz). ³C NMR (CDCl₃) δ: 176.3, 173.7, 172.4, 154.1, 131.7, 119.2,79.2, 76.9, 66.6, 66.3, 35.7, 32.4, 26.9, 26.4, 25.0, 22.7, 18.0, 13.4.

[0206] MS (Electrospray): 404.2 (M⁺+Na⁺).

EXAMPLE 11

[0207] Synthesis of(1′S,2′S,5′R,6′S)-3-Allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylicacid 6′-methoxycarbonyloxymethyl ester

[0208] The title compound was prepared according to General Procedure 1using chloromethyl methyl carbonate (which was obtained fromchloromethyl chloroformate as described by Patonay, T. et al, Synth.Commun. 1990, 20, 2865-2885 and Davidsen et al. J. Med. Chem. 1994, 37,4423-4429).

[0209] Colorless syrup.

[0210]¹H NMR (CDCl₃) δ: 5.93-5.78 (m, 1H), 5.72 (AB system, 2H),5.40-5.25 (AB system 2H), 5.33 (brs, 2H), 4.65 (m, 2H), 3.84 (s, 3H),2.68 (m, 1H), 2.50-2.25 (m, 2H), 2.22-1.90 (m, 3H), 1.55 (m, 1H).

EXAMPLE 12

[0211] Synthesis of(1′S,2′S,5′R,6′S)-3-Allyloxycarbonyl-5-oxo-oxazolidine-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylicacid 6′-(5-methyl-2-oxo-[1,3]dioxolen-4-enyl)methyl ester.

[0212] The title compound was prepared according to General Procedure 1using 4-bromomethyl-5-methyl-[1,3]dioxol-2-one [Alexander, J, U.S. Pat.No. 5,466,811 (1995)]. Flash chromatography of the crude (hexanes/ethylacetate 5:2) provided the ester. 64% yield. White foam.

[0213]¹H-NMR (CDCl₃) δ: 6.05-5.85 (m, 1H); 5.38-5.25 (m, 5H); 4.86 and4.79 (AB system, J=14.5 Hz, 2H); 4.63 (dc, J=5.9, 1.1 Hz, 2H); 2.61 (m,1H); 2.49-1.95 (m, 5H); 2.16 (s, 3H); 1.78-1.68 (m, 1H).

General Procedure 2

[0214] General Procedure for 2-Allyloxycarbonylamino-6-allyl Ester and2-Allyoxycarbonyl-oxazolidine Deprotection and Hydrochloride Formation.

[0215] The corresponding(1S,2S,5R,6S)-2-allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-ester 6-allyl or 2-allyoxycarbonyl-oxazolidine ester wasdissolved in dry dichloromethane (0.1 M solution) under nitrogen.1,3-Dimethylbarbituric acid (3.0 equiv) andtetrakis(triphenylphosphine)palladium(0) (0.03 equiv) were added and thesolution was heated at 35° C. for 2 h. After cooling to roomtemperature, the solvent was removed under vacuum and the resultingresidue was dissolved in a solution of ethyl acetate saturated withhydrogen chloride gas and stirred for 2 h. In the case where a solidappeared, the reaction was filtered. The filtrated material was washedwith ethyl acetate and ether, and dried to provide the product. In thecase where a solid did not appear, the solvent was removed under vacuum,ethyl ether was added and the mixture was stirred overnight. The solidwas filtered, washed thoroughly with ether and dried to provide theproduct.

EXAMPLE 13

[0216] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2-(3′-phthalidyl) ester hydrochloride

[0217] The title compound was prepared according to General Procedure2.83% Yield. White solid. Mixture of diastereomers.

[0218]¹H NMR (Methanol-d₄) δ: (mixture of diastereomers): 7.98-7.60 (m,4H), 7.59 (brs,1H), 2.38-2.21 (m, 2H), 2.17-2.04 (m, 4H), 1.66-1.58 (m,1H).

[0219]¹³C NMR (Methanol-d₄) δ; (mixture of diastereomers): 174.4, 170.4,170.3, 169.0, 145.0, 144.9, 136.6, 136.6, 133.0, 127.3, 127.3, 126.7,126.7, 125.2, 125.1, 95.6, 95.5, 67.1, 66.9, 33.6, 33.6, 31.6, 31.4,29.8, 29.8, 27.9, 27.8, 22.3, 22.3.

[0220] MS (Electrospray): 317.2 (M⁺+1).

EXAMPLE 14

[0221] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2-isopropyloxycarbonyloxymethyl ester hydrochloride

[0222] The title compound was prepared according to General Procedure2.41% Yield. White solid. mp 59-60° C.

[0223] [α]_(D) ²⁵=+11.4° (c=0.7, MeOH).

[0224]¹H NMR (Methanol-d₄) δ: 5.90 (brs, 2H), 4.88 (m, 1H), 2.33-2.01(m, 6H), 1.62-1.55 (m, 1H), 1.31 (d, 6H, J=6.2 Hz).

[0225]¹³C NMR (Methanol-d₄) δ: 173.0, 168.8, 153.1, 83.0, 73.2, 65.5,32.2, 29.9, 28.4, 26.3, 20.8, 20.3.

[0226] MS (Electrospray): 302.2 (M⁺+1).

EXAMPLE 15

[0227] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2-(4′-methoxy-benzoyloxy)methyl ester hydrochloride

[0228] The title compound was prepared according to General Procedure 2.51% Yield.

[0229]¹H-NMR (Methanol-d₄): 8.03 (dd, J=6.9, 2.0 Hz, 2H), 7.04 (dd,J=6.9, 2.1 Hz, 2H), 6.13 (q, J=5.1 Hz, 2H), 3.88 (s, 3H), 2.32-1.97 (m,6H), 1.57-1.30 (m, 1H).

[0230]¹³C-NMR (Methanol-d₄): 174.5, 170.5, 166.0, 133.2, 121.8, 115.7,115.2, 114.7, 82.4, 67.1, 56.2, 33.6, 31.5, 29.9, 27.8, 22.3.

EXAMPLE 16

[0231](1S,2S,5R,6S)-2-Allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-(naphthalene-2′-carbonyloxymethyl) ester hydrochloride

[0232] The title compound was prepared according to General Procedure 2.66% yield. Solid. m.p. 184-185° C.

[0233] IR (KBr) ν: 3400-2400, 2978, 1769, 1734, 1684, 1599, 1578, 1541,1447, 1410, 1283, 1203, 1076 cm⁻¹.

[0234]¹H NMR (Methanol-d₄) δ: 8.69 (brs, 1H), 8.02 (m, 4H), 7.63 (m,2H), 6.23 (AB system, 2H), 2.42-1.99 (m, 6H), 1.56 (m, 1H).

[0235]¹³C NMR (Methanol-d₄) δ: 174.7, 170.6, 166.6, 137.6, 134.0, 133.0,130.7, 130.3, 129.9, 129.1, 128.4, 127.2, 126.1, 82.7, 67.3, 33.8, 31.7,30.1, 27.9, 22.4.

[0236] MS (Electrospray): 392.2 (M⁺+Na), 370.1 (M⁺+H).

EXAMPLE 17

[0237] (1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2-(naphthalene-1′-carbonyloxymethyl) ester hydrochloride

[0238] The title compound was prepared according to General Procedure 2.91% yield. Solid. m.p. 212-213° C.

[0239] IR (KBr) ν: 3200-2400, 1767, 1732, 1682, 1581, 1531, 1512, 1447,1373, 1333, 1273, 1244, 1205, 1107, 908 cm⁻¹.

[0240]¹H NMR (Methanol-d₄) δ: 8.87 (d, 1H), 8.28 (dd, 1H), 8.16 (d, 1H),7.97 (m, 1H), 7.69-7.52 (m, 3H), 6.25 (s, 2H), 2.42-2.00 (m, 6H), 1.59(m, 1H).

[0241]¹³C NMR (Methanol-d₄) δ: 174.7, 170.7, 167.0, 136.0, 135.6, 132.8,132.4, 130.1, 129.5, 127.8, 126.4, 125.8, 82.6, 67.3, 33.9, 31.6, 30.1,28.0, 22.5.

[0242] MS (Electrospray): 392.1 (M⁺+Na), 370.1 (M⁺+H).

EXAMPLE 18

[0243] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2-cyclohexyloxycarbonyloxymethyl ester

[0244] The title compound was prepared according to General Procedure 2.63% yield. Solid.

[0245] IR (KBr) ν: 3500-2500, 2941, 2863, 1761, 1699, 1591, 1514, 1452,1319, 1280, 1253, 1188, 1096 cm⁻¹.

[0246]¹H NMR (Methanol-d₄) δ: 5.90 (s, 2H,), 4.67 (m, 1H), 2.35-1.27 (m,17H).

[0247]¹³C NMR (Methanol-d₄) δ: 174.7, 170.6, 154.8, 84.8, 79.5, 67.4,33.9, 32.6, 31.7, 30.2, 28.1, 26.5, 24.7, 22.7.

[0248] MS (Electrospray): 364.1 (M⁺+Na), 342.1 (M⁺+H).

EXAMPLE 19

[0249] Synthesis of(1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid6-tert-butylcarbonyloxymethyl ester hydrochloride

[0250] The title compound was prepared according to General Procedure 2using(1′S,2′S,5′R,6′S)-3-allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylicacid 6′-(tert-butylcarbonyloxy)methyl ester.

[0251] 74% Yield. White solid. mp 258° C. (dec.).

[0252] [α]_(D) ²⁵=+13.7° (c=1.0, MeOH).

[0253]¹H NMR (Methanol-d₄) δ: 5.75 (brs; 2H), 2.32-2.05 (m, 6H), 1.58(m, 1H), 1.19 (s, 9H).

[0254]¹³C NMR (Methanol-d₄) δ: 178.6, 172.6, 171.9, 81.2, 66.7, 39.7,34.4, 31.2, 30.7, 27.7, 27.2, 22.0.

[0255] MS (Electrospray): 300.1 (M⁺+H).

EXAMPLE 20

[0256] Synthesis of(1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid6-benzoyloxymethyl ester hydrochloride

[0257] The title compound was prepared according to General Procedure 2using(1′S,2′S,5′R,6′S)-3-allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylicacid 6′-(benzoyloxy)methyl ester.

[0258] 32% Yield. White solid. mp 230° C., dec.

[0259] [α]_(D) ²⁵+6.21° (c=0.66, MeOH).

[0260]¹H NMR (Methanol-d₄) δ: 8.03 (m, 2H), 7.64 (m, 1H), 7.54-7.46 (m,2H), 6.00 (AB system, 2H), 2.38-2.05 (m, 6H), 1.59-1.48 (m, 1H).

[0261]¹³C NMR (Methanol-d₄) δ: 171.0, 170.3, 164.9, 133.6, 129.3, 128.7,128.3, 79.6, 65.3, 33.1, 29.8, 29.2, 26.3, 20.5.

[0262] MS (Electrospray): 320.2 (M⁺+H), 342.1 (M⁺+Na⁺).

General Procedure 3

[0263] General Procedure for 2-allyloxycarbonyl-oxazolidine deprotectionand zwitterion formation.

[0264] The corresponding 2-allyloxycarbonyl-oxazolidine compound (1.0equiv) was dissolved in dry dichloromethane (0.1 M solution) undernitrogen. 1,3-Dimethylbarbituric acid (3.0 equiv for each allyl group tobe removed) and tetrakis (triphenylphosphine)palladium(0) (0.03 equiv)were added and the solution was heated at 35° C. for 2 h. After coolingto room temperature, the solvent was removed under vacuum and theresulting residue was dissolved in a solution of ethyl acetate saturatedwith hydrogen chloride gas and stirred for 2 h. In the case where asolid appeared, the reaction was filtered. The filtrated material waswashed with ethyl acetate and ether, and dried to provide the product asthe hydrochloride salt. In the case where a solid did not appear, thesolvent was removed under vacuum, ethyl ether was added and the mixturewas stirred overnight. The solid was filtered, washed thoroughly withether and dried to provide the product as the hydrochloride salt. Thehydrochloride salt was dissolved in the minimun ammount of dry methanoland filtered to remove any impurities. Propylene oxide (5 mL/mmol) wasadded to the homogeneous methanolic solution and the resulting mixturewas stirred overnight. The precipitate was filtered, and washed withmethanol and ethyl ether. Drying under high vacuum afforded the productas a zwitterion.

EXAMPLE 21

[0265] Synthesis of(1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid6-tert-butylcarbonyloxymethyl ester.

[0266] The title compound was prepared according to General Procedure 3using(1′S,2′S,5′R,6′S)-3-allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylicacid 6′-tert-butylcarbonyloxymethyl ester.

[0267] 46% Yield White solid. mp 205-206° C.

[0268] [α]_(D) ²⁵=+21.3° (c=1.0, 1N HCl).

[0269]¹H NMR (D₂O/TFA-d₁) δ: 5.56 (AB system, 2H), 2.23 (m, 1H),2.15-2.05 (m, 3H), 2.01-1.91 (m, 2H), 1.41 (m, 1H), 1.00 (s, 9H).

[0270]¹³C NMR (D₂O/TFA-d₄) δ: 179.2, 172.1, 171.6, 79.9, 65.4, 38.2,32.6, 29.5, 29.4, 25.9, 25.6, 20.6.

[0271] MS (Electrospray): 300.3 (M⁺+H), 322.3 (M⁺+Na)

EXAMPLE 22

[0272] Synthesis of(1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid6-benzoyloxymethyl ester.

[0273] The title compound was prepared according to General Procedure 3using(1′S,2′S,5′R,6′S)-3-allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2′-bicyclo[3.1.0]hexane-61-carboxylicacid 6′-benzoyloxymethyl ester.

[0274] 10% Yield. White solid. mp 210-212° C. (dec.)

[0275] [α]_(D) ²⁵=+5.6° (c=0.25, 1N HCl).

[0276]¹H NMR (D₂O/TFA-d₁) δ: 7.86 (dd, 2H, J=7.2, 1.2 Hz), 7.50 (m, 1H),7.36 (m, 2H), 5.83 (AB system, 2H), 2.29 (m, 1H), 2.13-1.89 (m, 5H),1.45 (m, 1H).

EXAMPLE 23

[0277] Synthesis of(1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid6-isopropyloxycarbonyloxymethyl ester.

[0278] The title compound was prepared according to General Procedure 3using(1′S,2′S,5′R,6′S)-3-allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylicacid 6′-isopropoxycarbonyloxymethyl ester.

[0279] 36% Yield. White solid. mp 196-197° C.

[0280] [α]_(D) ²⁵=+15.0° (c=0.18, 1N HCl).

[0281]¹H NMR (D₂O/TFA-d₁) δ: 5.49 (AB system, 2H), 4.67 (m, 1H), 2.19(m, 1H), 2.11-1.80 (m, 4H), 1.86 (t, 1H, J=2.8 Hz), 1.33 (m, 1H), 1.04(d, 6H, J=6.2 Hz).

[0282]¹³C NMR (D₂O/TFA-d₁) δ: 172.8, 171.9, 153.5, 82.2, 74.7, 65.5,32.8, 29.7, 29.6, 25.9, 20.7, 20.4.

[0283] MS (Electrospray): 302.2 (M⁺+H), 324.1 (M⁺+Na⁺)

EXAMPLE 24

[0284] Synthesis of(1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid6-n-butyryloxymethyl ester.

[0285] The title compound was prepared according to General Procedure 3using(1′S,2′S,5′R,6′S)-3-allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylicacid 6′-(n-butyryloxymethyl) ester. 50% Yield. White solid. mp 199-200°C.

[0286] [α]_(D) ²⁵=+10.8°(c=0.55, 1N HCl).

[0287]¹H NMR (D₂O/TFA-d₁) δ: 5.56 (AB system, 2H), 2.23 (t, 2H, J=7.2Hz), 2.22-1.96 (m, 5H), 1.91 (t, 1H, J=3.0 Hz), 1.48-1.34 (m, 3H), 0.71(t, 3H, J=7.1 Hz).

[0288] MS (Electrospray): 286.1 (M⁺+H), 308.21 (M⁺+Na⁺).

EXAMPLE 25

[0289] Synthesis of(1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid6-methoxycarbonyloxymethyl ester.

[0290] The tile compound was prepared according to General Procedure 3using (1′S,2′S,5′R,6′S)-3-allyloxycarbonyl-5oxo-oxazolidinone-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylic acid6′-(methoxycarbonyloxy)methyl ester.

[0291] White solid. mp 214-215° C.

[0292] [α]_(D) ²⁵=+17.3° (c=0.45, 1N HCl).

[0293]¹H NMR (D₂O/TFA-d₁) δ: 5.80 (AB system, 2H), 3.88 (s, 3H),2.51-2.43 (m, 1H), 2.36-2.23-(m, 3H), 2.14 (t, 1H, J=3.0 Hz), 1.72 (m,1H).

[0294]¹³C NMR (Methanol-d₄) δ: 171.5, 170.6, 155.0, 82.4, 65.8, 54.8,33.6, 30.2, 29.7, 26.8, 21.0.

[0295] MS (Electrospray): 274.1 (M⁺+H), 296.1 (M⁺+Na⁺)

EXAMPLE 26

[0296] Synthesis of(1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid6-(5′-methyl-2′-oxo-[1′,3′]dioxolen-4′-yl)methyl ester.

[0297] The tile compound was prepared according to General Procedure 3using(1′S,2′S,5′R,6′S)-3-allyloxycarbonyl-5-oxo-oxazolidine-4-spiro-2′-bicyclo[3.1.0]hexane-6′-carboxylicacid 6′-(5-methyl-2-oxo-[1,3]dioxolen-4-enyl)methyl ester. The crude waspurified by reverse phase chromatography using a C18 support elutingwith mixtures of methanol and water. White solid. Yield 22%.

[0298] mp 180° C. (decomposition).

[0299]¹H-NMR (D₂O) δ: 4.95 (s, 2H); 2.29-2.00 (m, 5H); 2.13 (s, 3H);1.94 (t, J=2.7 Hz, 1H); 1.50-1.35 (m, 1H).

[0300] [α]D₂₅=+5° (c=0.50, 1N HCl).

[0301] MS (Electrospray): 298 (M⁺+1).

General Procedure 4

[0302] General Procedure for Diesterification of(1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid

[0303](1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid (Example Preparation 2) (1.0 equiv) was dissolved in drydimethylformamide (0.5 M solution) under nitrogen and potassiumcarbonate or cesium carbonate (2.0 equiv) was added at room temperatureor 0° C. After 5 min, the corresponding halide (2.0 equiv) and sodiumiodide (1.0 equiv) were added. The reaction was vigorously stirred atroom temperature overnight. Water was added and the aqueous phase wasextracted with portions of ethyl acetate. The combined organic extractswere washed with cold water, dried over magnesium sulfate andconcentrated to dryness. The crude mixture was purified by silica gelflash-chromatography using the appropiate eluent (typically mixtures ofhexanes/ethyl acetate).

EXAMPLE 27

[0304](1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2,6-dipivaloyloxymethyl ester

[0305] The title compound was prepared according to General Procedure 4using commercially available chloromethyl pivalate.

[0306] 71% Yield. Colorless syrup.

[0307] [α]_(D) ²⁵=6.57° (c=1.4, CHCl₃).

[0308]¹H NMR (CDCl₃) δ: 5.82 (AB system, 2H), 5.74 (brs, 2H), 5.38 (brs,1H), 2.46-2.32 (m, 2H), 2.20-1.91 (m, 3H), 1.76 (t, 1H, J=2.9 Hz), 1.42(brs, 9H), 1.27 (m, 1H), 1.21 (s, 18H).

[0309]¹³C NMR (CDCl₃) δ: 177.0, 176.2, 171.5, 170.9, 155.1, 80.1, 79.6,66.4, 38.7, 34.9, 32.4, 28.9, 28.2, 28.0, 26.8, 26.5, 20.8.

[0310] MS (Electrospray): 536.1 (M⁺+Na).

EXAMPLE 28

[0311](1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2,6-dibenzoyloxymethyl ester

[0312] The title compound was prepared according to General Procedure 4using chloromethyl benzoate (which was obtained as described by Davidsenet al. J. Med. Chem. 1994, 37, 4423-4429).

[0313] 31% Yield. Colorless syrup.

[0314] [α]_(D) ²⁵=−8.42° (c=1.08, CHCl₃).

[0315]¹H NMR (CDCl₃) δ: 8.03-7.97 (m, 4H), 7.57-7.48 (m, 2H), 7.42-7.33(m, 4H), 6.01 (brs, 2H), 5.90 (brs, 2H), 5.55 (brs, 1H), 2.51-2.35 (m,2H), 2.09-1.83 (m, 3H), 1.75 (t, 1H, J=2.7 Hz), 1.24 (m, 1H), 1.24 (brs,9H).

[0316]¹³C NMR (CDCl₃) δ: 171.7, 171.0, 165.1, 165.0, 155.1, 133.6,129.9, 129.6, 128.7, 128.4, 80.2, 79.4, 66.3, 34.9, 32.0, 29.0; 28.0,26.3, 20.7.

[0317] MS (Electrospray): 576.1 (M⁺+Na).

EXAMPLE 29

[0318](1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2,6-diisopropyloxycarbonyloxymethyl ester

[0319] The title compound was prepared according to General Procedure 4using chloromethyl isopropyl carbonate (which was obtained fromchloromethyl chloroformate as described by Patonay, T. et al, Synth.Commun. 1990, 20, 2865-2885 and Davidsen et al. J. Med. Chem. 1994, 37,4423-4429).

[0320] 36% Yield. Colorless syrup.

[0321] [α]_(D) ²⁵=−5.40° (c=1.0, CHCl₃).

[0322]¹H NMR (CDCl₃) δ: 5.81 (brs, 2H), 5.73 (brs, 2H), 5.37 (brs, 1H),4.91 (m, 2H), 2.44 (m, 2H), 2.11-1.98 (m, 3H), 1.79 (t, 1H, J=2.8 Hz),1.42 (brs, 9H), 1.34 (d, 6H, J=2.8 Hz), 1.30 (d, 6H, J=2.8 Hz), 1.28 (m,1H).

[0323]¹³C NMR (CDCl₃) δ: 171.3, 170.8, 153.3, 153.2, 82.4, 81.6, 73.0,72.9, 66.3, 34.5, 32.2, 29.0, 28.1, 26.5, 21.5, 21.5, 20.7.

[0324] MS (Electrospray): 540.1 (M⁺+Na).

EXAMPLE 30

[0325](1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2,6-di-(1′-isopropyloxycarbonyloxylethyl) ester

[0326] The title compound was prepared according to General Procedure 4using 1-chloroethyl isopropyl carbonate (which was obtained from1-chloroethyl chloroformate as described by Patonay, T. et al, Synth.Commun. 1990, 20, 2865-2885 and Davidsen et al. J. Med. Chem. 1994, 37,4423-4429).

[0327] 29% Yield. Cream syrup. Mixture of diastereomers.

[0328]¹H NMR (CDCl₃) δ (mixture of diastereomers): 6.83-6.68 (m, 2H),5.09 (brs, 1H), 4.89 (m, 2H), 2.49-2.33 (m, 2H), 2.19-1.90 (m, 3H),1.73-1.64 (m, 1H), 1.55-1.48 (m, 6H), 1.43 (brs, 9H), 1.32 (d, 6H, J=6.3Hz), 1.29 (d, 6H, J=6.3 Hz), 1.26 (m, 1H).

[0329]¹³C NMR (CDCl₃) δ (mixture of diastereomers): 170.7, 170.3, 170.2,155.0, 152.5, 92.1, 92.0, 91.2, 91.2, 72.8, 72.7, 66.5, 66.4, 35.0,34.9, 32.4, 28.8, 28.5, 28.2, 27.0, 26.9, 26.5, 26.4, 21.2, 21.1, 21.0,21.0, 20.9, 19.9, 19.5, 19.4.

[0330] MS (Electrospray): 568.2 (M⁺+Na).

EXAMPLE 31

[0331](1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2,6-di-(1′-ethoxycarbonyloxylethyl) ester

[0332] The title compound was prepared according to General Procedure 4using commercially available 1-chloroethyl ethyl carbonate.

[0333] 47% Yield. Cream syrup. Mixture of diastereomers.

[0334]¹H NMR (CDCl₃) δ (mixture of diastereomers): 6.84-6.65 (m, 2H),5.21 (brs, 1H), 4.28-4.16 (m, 4H), 2.46 (m, 1H), 2.33 (m, 1H), 2.21-1.85(m, 3H), 1.70 (m, 1H), 1.52-1.48 (m, 6H), 1.42 (s, 9H), 1.34-1.27 (m,6H), 1.25 (m,1H).

[0335]¹³C NMR (CDCl₃) δ (mixture of diastereomers): 170.6, 170.2, 170.2,170.1, 154.9, 152.8, 92.1, 92.0, 91.2, 91.2, 66.4, 66.3, 64.4, 64.3,34.8, 32.2, 28.7, 28.5, 28.1, 26.8, 26.7, 26.3, 26.2, 21.0, 20.9, 20.8,20.7, 19.4, 19.3, 14.0.

[0336] MS (Electrospray): 540.2 (M⁺+Na).

EXAMPLE 32

[0337](1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2,6-di-(3′-phthalidyl) ester

[0338] The title compound was prepared according to General Procedure 4using 3-bromophthalide (which was obtained from phthalide as describedby Koten et al. Org. Synth. Coll. Vol. V, 145-147).

[0339] 89% Yield. White foamy solid.

[0340]¹H NMR (CDCl₃) δ (mixture of diastereomers): 7.92 (brd, 2H, J=7.0Hz, 2H), 7.90-7.55 (m, 6H), 7.48 (brs, 1H), 7.39 (brs, 1H), 5.27-5.11(br, 1H), 2.63-1.99 (m, 5H), 1.81-1.76 (m, 1H), 1.36 (brs, 9H),1.28-1.21 (m, 1H).

[0341]¹³C NMR (CDCl₃) δ (mixture of diastereomers): 171.3, 170.8, 170.6,167.6, 154.9, 144.0, 134.8, 131.2, 126.2, 126.2, 125.6, 125.6, 125.1,124.2, 123.8, 123.5, 93.4, 92.7, 66.4, 35.0, 32.2, 29.4, 29.3, 29.0,28.9, 28.0, 26.6, 26.0, 20.9, 20.7.

[0342] MS (Electrospray): 450.1 (M⁺+H-BOC), 572.2 (M⁺+Na)

EXAMPLE 33

[0343](1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2,6-dimethoxycarbonyloxymethyl ester.

[0344] The title compound was prepared according to General Procedure 4using chloromethyl methyl carbonate (which was obtained fromchloromethyl chloroformate as described by Patonay, T. et al, Synth.Commun. 1990, 20, 2865-2885 and Davidsen et al. J. Med. Chem. 1994, 37,4423-4429).

[0345]¹H NMR (CDCl₃) δ: 5.82 (s, 2H), 5.74 (s, 2H), 3.84 (s, 3H), 3.82(s, 3H), 2.55-2.41 (m, 2H), 2.27-1.92 (m, 3H), 1.77 (t, 1H, J=3.0 Hz),1.42 (s, 9H), 1.31-1.18 (m, 1H).

EXAMPLE 34

[0346](1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2,6-diisobutyryloxymethyl ester

[0347] The title compound was prepared according to General Procedure 4using chloromethyl isobutyrate (which was obtained using a similarprocedure to the one described by Davidsen et al. J. Med. Chem. 1994,37, 4423-4429). 44% Yield.

[0348]¹H-NMR (CDCl₃) δ: 5.80 (s, 2H), 5.71 (s, 2H), 5.14 (brs, 1H), 2.55(sept., 2H, J=7.0 Hz), 2.39 (m, 2H), 2.05-1.90 (m, 3H), 1.74 (t, J=2.8Hz, 1H), 1.41 (s, 9H), 1.28 (m, 1H), 1.20 (s, 6H), 1.16 (s, 6H).

[0349]¹³C-NMR (CDCl₃) δ: 175.2, 175.1, 172.7, 172.0, 155.1, 79.9, 79.3,66.5, 34.9, 33.6, 32.3, 28.8, 28.1, 26.5, 20.8, 18.5.

EXAMPLE 35

[0350](1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-di-(n-butyryloxymethyl)ester

[0351] The title compound was prepared according to General Procedure 4using commercially available chloromethyl butyrate.

[0352] 71% yield. Oil.

[0353] IR (KBr) ν: 3389, 2974, 2940, 2880, 1761, 1717, 1506, 1456, 1423,1368, 1254, 1169, 1105, 995 cm⁻¹.

[0354]¹H NMR (CDCl₃) δ: 5.77 (s, 2H), 5.69 (s, 2H), 5.31 (brs, 1H), 2.39(m, 2H), 2.32 (t, 2H, J=7.4 Hz), 2.31 (t, 2H, J=7.4 Hz), 2.12-1.87 (m,3H), 1.73 (t, J=2.8 Hz, 1H), 1.63 (st, 2H, J=7.4 Hz), 1.62 (st, 2H,J=7.4 Hz), 1.38 (s, 9H), 1.20 (m, 1H), 0.92 (t, 3H, J=7.4 Hz), 0.91 (t,3H, J=7.4 Hz).

[0355]¹³C NMR (CDCl₃) δ: 172.2, 172.1, 171.6, 171.0, 155.0, 80.3, 79.7,79.0, 66.2, 35.6, 34.9, 32.2, 28.9, 28.1, 26.5, 20.7, 18.0, 13.4.

[0356] MS (Electrospray): 508.2 (M⁺+Na).

EXAMPLE 36

[0357](1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-di-(2′-naphthoyloxymethyl)ester

[0358] The title compound was prepared according to General Procedure 4using chloromethyl 2-napthtoate (which was obtained using a similarprocedure to the one described by Davidsen et al. J. Med. Chem. 1994,37, 4423-4429). 59% yield. Oil.

[0359] IR (KBr) ν: 3382, 3061, 2980, 2937, 2874, 1736, 1630, 1599, 1508,1471, 1423, 1390, 1368, 1282, 1153, 1128, 1082, 978 cm⁻¹.

[0360]¹H NMR (CDCl₃) δ: 8.63 (m, 2H), 8.05 (m, 2H), 7.93 (m, 2H), 7.85(d, 4H), 7.56 (m, 4H), 6.12 (s, 2H), 6.02 (s, 2H), 5.34 (brs, 1H),2.58-2.42 (m, 2H), 2.28-1.88 (m, 4H), 1.82 (t, 1H, J=2.8 Hz), 1.39 (s,9H).

[0361]¹³C NMR (CDCl₃) δ: 171.7, 171.0, 165.3, 165.2, 155.0, 135.8,132.3, 131.8, 129.4, 128.6, 128.2, 127.7, 126.7, 126.0, 125.2, 80.43,79.6, 66.4, 35.0, 32.3, 29.0, 28.0, 26.5, 20.9.

[0362] MS (Electrospray): 676.1 (M⁺+Na).

EXAMPLE 37

[0363](1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-di-(1′-naphthoyloxymethyl)ester

[0364] The title compound was prepared according to General Procedure 4using chloromethyl 1-napthtoate (which was obtained using a similarprocedure to the one described by Davidsen et al. J. Med. Chem. 1994,37, 4423-4429).

[0365] 63% yield. Oil.

[0366] IR (KBr) ν: 3387, 3053, 2980, 2937, 2874, 1732, 1593, 1576, 1510,1456, 1423, 1392, 1368, 1332, 1278, 1240, 1159, 1115, 1001 cm⁻¹.

[0367]¹H NMR (CDCl₃) δ: 8.98 (t, 1H), 8.29 (m, 1H), 8.08 (d, 1H), 7.89(d, 1H), 7.69-7.47 (m, 3H), 6.16 (s, 2H), 6.06 (s, 2H), 5.20 (br s, 1H),2.60-2.45 (m, 2H), 2.30-1.92 (m, 3H), 1.83 (t, 1H, J=3.0 Hz), 1.31 (s,9H), 1.29 (m, 1H).

[0368]¹³C NMR (CDCl₃) δ: 171.7, 171.1, 165.6, 155.1, 134.4, 134.3,133.8, 131.6, 131.3, 128.6, 128.2, 128.1, 126.3, 125.6, 125.5, 125.1,124.4, 80.4, 79.7, 66.5, 35.1, 32.4, 29.0, 28.1, 26.6, 20.9.

[0369] MS (Electrospray): 676.2 (M⁺+Na).

EXAMPLE 38

[0370](1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid dicyclohexyloxycarbonyloxymethyl ester

[0371] The title compound was prepared according to General Procedure 4using chloromethyl cyclohexyl carbonate (which was obtained fromchloromethyl chloroformate as described by Patonay, T. et al, Synth.Commun. 1990, 20, 2865-2885 and Davidsen et al. J. Med. Chem. 1994, 37,4423-4429).

[0372] 55% yield. Oil.

[0373] IR (KBr) ν: 3381, 2940, 2863, 1759, 1713, 1506, 1454, 1425, 1368,1321, 1259, 1153, 1105 cm⁻¹.

[0374]¹H NMR (CDCl₃) δ: 5.80 (s, 2H), 5.72 (s, 2H), 5.21 (br s, 1H),4.65 (m, 2H), 2.51-2.41 (m, 2H), 2.25-1.65 (m, 12H), 1.60-1.20 (m, 13H),1.41 (s, 9H).

[0375]¹³C NMR (CDCl₃) δ: 171.3, 170.7, 155.0, 153.3, 153.2, 82.6, 81.8,80.5, 77.8, 77.7, 66.4, 35.1, 32.3, 31.3, 31.2, 29.0, 28.1, 26.6, 25.1,23.4, 20.8.

[0376] MS (Electrospray): 620.1 (M⁺+Na).

EXAMPLE 39

[0377](1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2,6-di-(1′-cyclohexyloxycarbonyloxy-ethyl) ester

[0378] The title compound was prepared according to General Procedure 4using 1-chloroethyl cyclohexyl carbonate (which was obtained from1-chloroethyl chloroformate as described by Patonay, T. et al, Synth.Commun. 1990, 20, 2865-2885 and Davidsen et al. J. Med. Chem. 1994, 37,4423-4429).

[0379] 43% yield. Oil.

[0380] IR (KBr) ν: 3383, 2940, 2863, 1760, 1716, 1506, 1450, 1367, 1321,1277, 1259, 1163, 1078 cm⁻¹.

[0381]¹H NMR (CDCl₃, mixture of 4 diastereomers) δ: 6.78 (q, 1H), 6.71(q, 1H), 5.10 (brs, 1H), 4.63 (m, 2H), 2.50-2.33 (m, 2H), 2.22-1.64 (m,12H), 1.60-1.20 (m, 19H), 1.42 (s, 9H).

[0382]¹³C NMR (CDCl₃, mixture of 4 diastereomers) δ: 170.6, 170.3,170.2, 155.0, 152.4, 92.1, 92.0, 91.2, 80.3, 77.5, 77.4, 66.5, 66.4,35.5, 34.9, 34.8, 32.3, 31.3, 28.8, 28.7, 28.5, 28.2, 27.0, 26.8, 26.4,26.3, 25.1, 23.5, 21.1, 21.0, 20.9, 20.8, 19.5, 19.4.

[0383] MS (Electrospray): 648.1 (M⁺+Na).

EXAMPLE 40

[0384](1S,2S,5R,6S)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2,6-diethoxycarbonyloxymethyl ester

[0385] The title compound was prepared according to General Procedure 4using chloromethyl ethyl carbonate (which was obtained from chloromethylchloroformate as described by Patonay, T. et al, Synth. Commun. 1990.,20, 2865-2885 and Davidsen et al. J. Med. Chem. 1994, 37, 4423-4429).

[0386] 70% yield. Oil.

[0387] IR (KBr) ν: 3389, 2984, 2941, 2876, 1763, 1713, 1506, 1456, 1425,1392, 1369, 1263, 1153, 1001 cm¹.

[0388]¹H NMR (CDCl₃) δ: 5.80, 5.79 (s, 2H), 5.72, 5.71 (s, 2H), 5.28 (brs, 1H), 4.24, 4.23 (q, 2H), 4.22, 4.21 (q, 2H), 2.50-1.88 (m, 6H), 1.76(m, 1H), 1.40 (s, 9H), 1.32, 1.31 (t, 3H), 1.30, 1.29 (t, 3H).

[0389]¹³C NMR (CDCl₃) δ: 171.3, 170.7; 155.0, 153.8, 153.7, 82.6, 81.8,80.4, 66.4, 64.7, 35.1, 32.3, 29.0, 28.1, 26.5, 20.8, 14.0.

[0390] MS (Electrospray): 512.2 (M⁺+Na).

EXAMPLE 41

[0391] (1S,2S,5R,6S)-Bis-(5-methyl-2-oxo-[1,3]dioxolen-4-ylmethyl)2-tert-butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylate

[0392] The title compound was prepared according to General Procedure 4using cesium carbonate and 4-bromomethyl-5-methyl-[1,3]dioxolen-2-one(which was obtained as described in Alexander, J., U.S. Pat. No.5,466,811, 1995).

[0393] 34% yield as a white foam.

[0394]¹H-NMR (CDCl₃) δ: 5.25 (bs, 1H); 4.89 (s, 2H); 4.80 (s, 2H);2.46-2.36 (m, 2H); 2.17 (s, 3H); 2.15 (s, 3H); 2.15-1.91 (m, 3H); 1.72(t, J=2.9 Hz, 1H); 1.38 (s, 9H); 1.30-1.07 (m, 1H).

General Procedure 5

[0395] General Procedure for 2-tert-Butoxycarbonylamino Deprotection andHydrochloride Formation

[0396] The corresponding(1S,2S,5R,6S)-2-tert-butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylicester was dissolved in a solution of ethyl acetate saturated withhydrogen chloride gas. The mixture was stirred at room temperatureovernight. The reaction was evaporated to dryness. The resulting residuewas dissolved in the minimum amount of ethyl acetate and triturated withdiethyl ether. The precipitate formed was filtered, washed with etherand dried under vacuum to provide the product.

EXAMPLE 42

[0397] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-dipivaloyloxymethyl ester hydrochloride

[0398] The title compound was prepared according to General Procedure 5.84% Yield. Foamy white solid. mp 49-50° C.

[0399] [ ]D²⁵=+8.05° (c=0.41, MeOH).

[0400]¹H NMR (Methanol-d₄) δ: 5.92 (brs, 2H), 5.74 (brs, 2H), 2.27-2.17(m, 6H), 1.62 (m, 1H), 1.23 (s, 9H), 1.19 (s, 9H).

[0401]¹³C NMR (Methanol-d₄) δ: 178.1, 175.1, 171.4, 170.0, 82.0, 81.1,66.8, 39.8, 39.7, 34.1, 31.2, 30.6, 27.8, 27.4 (2 t-Bu), 22.1.

[0402] MS (Electrospray): 414.3 (M⁺+H).

EXAMPLE 43

[0403] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid,2,6-dibenzoyloxymethyl ester hydrochloride

[0404] The title compound was prepared according to General Procedure5.87% Yield. White foamy solid. mp 73° C.

[0405] [α]_(D) ²⁵=−6.30° (c=1.0, MeOH).

[0406]¹H NMR (Methanol-d₄) δ: 8.09-8.00 (m, 4H), 7.72-7.63 (m, 2H),7.57-7.47 (m, 4H), 6.16 (AB system, 2H), 5.99 (AB system, 2H), 2.38-2.01(m, 6H), 1.55 (m, 1H).

[0407]¹³C NMR (Methanol-d₄) δ: 171.4, 170.2, 166.4, 166.3, 135.3, 135.1,130.9, 130.8, 130.2, 129.9, 129.8, 129.5, 82.6, 81.2, 67.0, 34.2, 31.3,30.6, 28.6, 27.7, 22.1.

[0408] MS (Electrospray): 454.3 (M⁺+H).

EXAMPLE 44

[0409] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-diisopropyloxycarbonyloxymethyl ester hydrochloride

[0410] The title compound was prepared according to General Procedure5.86% Yield. White foamy solid. mp 52° C.

[0411] [α]_(D) ²⁵=+1.40° (c=1.0, MeOH).

[0412]¹H NMR (Methanol-d₄) δ: 5.91 (brs, 2H), 4.74 (AB system, 2H),4.98-4.80 (m, 2H), 2.37-2.12 (m, 6H), 1.63 (m, 1H), 1.30 (d, 6H, J=6.2Hz), 1.28 (d, 6H, J=6.2 Hz).

[0413]¹³C NMR (Methanol-d₄) δ: 171.3, 170.1, 154.8, 154.6, 84.6, 83.3,74.7, 74.2, 67.0, 34.2, 31.2, 30.7, 27.8, 22.1, 21.9, 21.8.

[0414] MS (Electrospray): 418.2 (M⁺+H)

EXAMPLE 45

[0415] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-di-(1′-isopropyloxycarbonyloxylethyl) ester hydrochloride

[0416] The title compound was prepared according to General Procedure5.83% Yield. Foamy pale cream solid. Mixture of diastereomers.

[0417]¹H NMR (Methanol-d₄) δ (mixture of diastereomers): 6.82 (m, 1H),6.71 (m, 1H), 4.88 (m, 2H), 2.33-2.05 (m, 6H), 1.62-1.57 (m, 3H), 1.60(m, 1H), 1.50-1.47 (m, 3H), 1.34-1.23 (m, 12H).

[0418]¹³C NMR (Methanol-d₄) δ (mixture of diastereomers): 171.0, 171.0,170.8, 169.7, 154.2, 154.2, 94.7, 94.5, 93.0, 93.0, 74.5, 74.0, 67.1,34.4, 33.9, 31.5, 31.3, 30.7, 30.6, 30.5, 30.4, 30.1, 28.1, 28.0, 22.4,22.3, 22.0, 22.0, 19.8, 19.6.

[0419] MS (Electrospray): 446.2 (M⁺+H), 469.2 (M⁺+Na).

EXAMPLE 46

[0420] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-di-(1′-ethoxycarbonyloxylethyl) ester hydrochloride

[0421] The title compound was prepared according to General Procedure5.88% Yield. Foamy white solid.

[0422]¹H NMR (Methanol-d₄) δ (mixture of diastereomers): 6.81 (m, 1H),6.72 (m, 1H), 4.28-4.12 (m, 4H), 2.33-2.07 (m, 6H), 1.61-1.55 (m, 3H),1.58 (m, 1H), 1.49-1.46 (m, 3H), 1.34-1.23 (m, 12H).

[0423]¹³C NMR (Methanol-d₄) δ (mixture of diastereomers): 170.9, 170.8,170.7, 169.5, 154.6, 154.5, 94.6, 94.5, 93.0, 67.0, 65.9, 65.5, 34.2,33.8, 33.8, 31.4, 31.1, 30.6, 30.5, 30.4, 30.3, 27.9, 27.9, 27.8, 27.8,22.2, 22.2, 22.1, 22.1, 19.6, 19.4, 14.4.

[0424] MS (Electrospray): 418.2 (M⁺+H), 440.2 (M⁺+Na).

EXAMPLE 47

[0425] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-di-(3′-phthalidyl) ester hydrochloride

[0426] The title compound was prepared according to General Procedure5.91% Yield. White solid. Mixture of diastereomers.

[0427]¹H NMR (Methanol-d₄) δ (mixture of diastereomers): 7.96-7.71 (m,8H), 7.59 (brs,1H), 7.44 (brs, 1H), 2.56-2.12 (m, 6H), 1.71-1.62 (m, 1H)

[0428]¹³C NMR (Methanol-d₄) δ (mixture of diastereomers): 170.0, 169.8,168.6, 168.6, 168.0, 167.5, 144.2, 143.4, 135.1, 134.8, 131.6, 131.2,125.9, 125.8, 125.2, 124.9, 123.8, 123.7, 94.1, 93.1, 65.6, 60.1, 33.1,33.0, 32.8, 32.7, 29.9, 29.7, 29.4, 29.3, 26.4, 20.7, 20.6.

[0429] MS (Electrospray): 450.1 (M⁺+H), 472.1 (M⁺+Na).

EXAMPLE 48

[0430] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-dimethoxycarbonyloxymethyl ester hydrochloride

[0431] The title compound was prepared according to General Procedure 5.White solid mp 150° C., dec.

[0432] [α]_(D) ²⁵=+14.2° (c 1.54, MeOH).

[0433]¹H NMR (Methanol-d₄) δ: 5.92 (AB system, 2H), 5.75 (AB system,2H), 3.84 (s, 3H), 3.80 (s, 3H), 2.37-2.10 (m, 6H), 1.62-1.56 (m, 1H).

EXAMPLE 49

[0434] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-diisobutyryloxymethyl ester hydrochloride

[0435] The title compound was prepared according to General Procedure5.44% Yield. White solid. mp 224-226° C.

[0436] [α]_(D) ²⁵=+26.3° (c=0.65, MeOH).

[0437]¹H-NMR (Methanol-d₄) δ: 5.91 (s, 2H), 5.74 (m, 2H), 2.57 (sept,J=7.0 Hz, 2H), 2.31-2.11 (m, 6H), 1.57 (m, 1H), 1.17 (t, J=6.8 Hz, 12H)

[0438]¹³C-NMR (Methanol-d₄) δ: 178.6, 178.3, 171.9, 169.4, 80.9, 80.2,65.7, 33.6, 33.5, 32.8, 30.0, 29.7, 29.6, 29.2, 26.2, 21.0, 18.2, 17.8.

[0439] MS (Electrospray): 386.2 (M⁺+H).

EXAMPLE 50

[0440] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-dipropanoyloxymethyl ester hydrochloride

[0441] The title compound was prepared according to General Procedure5.87% yield. Oil.

[0442] IR (KBr) ν: 3500-2500, 2973, 2880, 1770, 1589, 1520, 1462, 1427,1342, 1263, 1157, 1101 cm⁻¹.

[0443] H NMR (Methanol-d₄) δ: 5.91 (s, 2H), 5.74 (s, 2H), 2.41 (t, 2H,J=7.2 Hz), 2.34 (t, 2H, J=7.2 Hz), 2.37-2.05 (m, 6H), 1.65 (st, 4H,J=7.2 Hz), 1.56 (m, 1H), 0.97 (t, 3H, J=7.2 Hz), 0.95 (t, 3H, J=7.2 Hz).

[0444]¹³C NMR (Methanol-d₄) δ: 173.7, 173.6, 171.6, 170.2, 82.0, 80.8,67.0, 36.6, 36.5, 34.2, 31.4, 30.7, 27.9, 22.2, 19.3, 19.2, 14.0.

[0445] MS (Electrospray): 385.17.

EXAMPLE 51

[0446] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-di-(2′-naphthoyloxymethyl) ester hydrochloride

[0447] The title compound was prepared according to General Procedure5.92% yield. Solid. m.p. 125-127° C.

[0448] IR (KBr) ν: 3500-2500, 2916, 2851, 1714, 1631, 1598, 1510, 1469,1354, 1279, 1226, 1152, 1076 cm⁻¹.

[0449]¹H NMR (Methanol-d₄) δ: 8.62 (d, 2H), 7.95 (m, 8H), 7.60 (m, 4H),6.21 (AB system, 2H), 6.04 (AB system, 2H), 2.43-2.01 (m, 6H), 1.57 (m,1H).

[0450]¹³C NMR (Methanol-d₄) δ: 171.7, 170.4, 166.7, 166.6, 137.6, 137.5,134.0, 133.0, 132.8, 130.6, 130.5, 130.3, 130.2, 129.8, 129.7, 129.0,128.4, 128.3, 127.5, 127.1, 126.0, 82.8, 81.4, 67.2, 34.4, 31.5, 30.8,27.9, 22.3.

[0451] MS (Electrospray): 554.1 (M⁺+H).

EXAMPLE 52

[0452] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-di-(1′-naphthoyloxymethyl) ester hydrochloride

[0453] The title compound was prepared according to General Procedure5.93% yield. Solid. m.p. 92-94° C.

[0454] IR (KBr) ν: 3407, 3054, 2947, 2880, 1732, 1593, 1578, 1512, 1462,1427, 1346, 1317, 1278, 1242, 1169, 1113 cm⁻¹.

[0455]¹H NMR (Methanol-d₄) δ: 8.85 (m, 2H), 8.23 (m, 2H), 8.15 (m, 2H),7.95 (m, 2H), 7.67-7.47 (m, 6H), 6.24 (AB system, 2H), 6.06 (AB system,2H), 2.45-2.05 (m, 6H), 1.59 (m, 1H).

[0456]¹³C NMR (Methanol-d₄) δ: 171.7, 170.4, 167.0, 166.9, 136.0, 135.8,135.5, 132.8, 132.4, 132.3, 130.1, 130.0, 129.5, 129.3, 127.8, 127.7,126.5, 126.4, 126.2, 125.8, 125.7, 82.7, 81.4, 67.2, 34.4, 31.5, 30.8,27.9, 22.3.

[0457] MS (Electrospray): 576.2 (M⁺+Na), 554.2 (M⁺+H).

EXAMPLE 53

[0458] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-dicyclohexyloxycarbonyloxymethyl ester

[0459] The title compound was prepared according to General Procedure5.93% yield. Solid.

[0460] IR (KBr) ν: 3500-2500, 2941, 2863, 1759, 1585, 1520, 1454, 1427,1319, 1253, 1157, 1097 cm⁻¹.

[0461]¹H NMR (Methanol-d₄) δ: 5.90 (AB system, 2H), 5.74 (AB system,2H), 4.66 (m, 2H, 2 CH), 2.35-2.10 (m, 6H), 2.00-1.67 (m, 8H), 1.62-1.30(m, 13H).

[0462]¹³C NMR (Methanol-d₄) δ: 171.4, 170.1, 154.8, 154.6, 84.9, 83.6,79.3, 78.9, 67.0, 34.3, 32.5, 32.4, 31.5, 30.8, 28.0, 26.4, 24.6, 22.2.

[0463] MS (Electrospray): 498.2 (M⁺+H).

EXAMPLE 54

[0464] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-di-(1′-cyclohexyloxycarbonyloxyethyl) ester hydrochloride

[0465] The title compound was prepared according to General Procedure5.88% yield. Solid.

[0466] IR (KBr) ν: 3500-2500, 2941, 2863, 1759, 1585, 1518, 1450, 1427,1379, 1359, 1317, 1256, 1190, 1078 cm⁻¹.

[0467]¹H NMR (Methanol-d₄, mixture of 4 diastereomers) δ: 6.81 (q, 1H),6.69 (q, 1H), 4.61 (m, 2H), 2.40-1.20 (m, 33H).

[0468]¹³C NMR (Methanol-d₄, mixture of 4 diastereomers) δ: 171.0, 170.9,170.3, 169.6, 154.2, 154.1, 94.6, 94.5, 93.0, 79.0, 78.5, 67.1, 34.5,33.9, 32.5, 31.5, 31.2, 30.7, 30.6, 30.5, 30.4, 28.1, 28.0, 26.4, 24.6,22.4, 22.3, 22.2, 19.8, 19.6.

[0469] MS (Electrospray): 548.2 (M⁺+Na), 526.2 (M⁺+H).

EXAMPLE 55

[0470] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-diethoxycarbonyloxymethyl ester hydrochloride

[0471] The title compound was prepared according to General Procedure5.84% yield. Oil.

[0472]¹H NMR (CDCl₃) δ: 5.91 (m, AB system, 2H), 5.75 (m, AB system,2H), 4.81 (brs, 1H), 4.26 (q, 2H), 4.21 (q, 2H), 2.40-2.10 (m, 6H), 1.63(m, 1H), 1.31 (t, 3H), 1.29 (t, 3H).

[0473]¹³C NMR (CDCl₃) δ: 171.5, 170.2, 155.4, 155.3, 84.8, 83.5, 67.1,66.3, 66.0, 34.3, 31.4, 30.8, 27.9, 22.2, 14.6.

[0474] MS (Electrospray): 412.1 (M⁺+Na).

EXAMPLE 56

[0475] (1S,2S,5R,6S)-Bis-(5-methyl-2-oxo-[1,3]dioxolen-4-ylmethyl)2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylate hydrochloride

[0476] The title compound was prepared according to General Procedure 5.

[0477] 60% yield as a white solid.

[0478]¹H-NMR (CDCl₃) δ: 5.14 (s, 2H); 4.93 (m, 2H); 2.27-2.08 (m, 6H);2.19 (s, 3H); 2.13 (s, 3H); 1.54-1.44 (m, 1H).

[0479]¹³C-NMR (CDCl₃) δ: 171.2, 169.3, 152.2, 152.1, 141.2, 140.2,133.3, 132.4, 66.3, 55.9, 54.2, 32.9, 30.1, 29.5, 26.6, 21.7, 9.3, 9.2.

EXAMPLE 57

[0480] (1S,2S,5R,6S)-Bis-(5-methyl-2-oxo-[1,3]dioxolen-4-ylmethyl)2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylate ethanesulfonic acid

[0481] Trifluoroacetic acid (TFA) (9.07 mL, 118 mmol) was added to asolution of (1S,2S,5R,6S)-bis-(5-methyl-2-oxo-[1,3]dioxolen-4-ylmethyl)2-tert-butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylate (6.00g, 11.8 mmol, crude) in CH₂Cl₂ (60 mL) and stirred for 4 h. Theresulting solution was partitioned between CH₂Cl₂ (50 mL) and H₂O (130mL). An aqueous solution of NaHCO₃ (130 mL, 1.0 M) was then added. Thephases were separated, and the aqueous phase was extracted with CH₂Cl₂(50 mL). The combined organics were dried (MgSO₄) and filtered.Ethanesulfonic acid (EtSO₃H) (0.96 mL, 11.8 mmol) was then addedfollowed by seed crystals. The solution was concentrated to a slurry(total weight of 60 g) and stirred at rt for 1 h. Diethyl ether (60 mL)was then added. The resulting slurry was stirred at rt for 2.5 h,filtered and dried under vacuum at 45° C. to afford 4.43 g (72%) of thetitle compound as a white crystalline solid.

[0482] [α]D=−1.92 (c 2.0, MeOH).

[0483]¹H NMR (CD₃OD) δ: 5.18 and 5.15 (AB quartet, JAB=13.8 Hz, 2H),4.98 and 4.93 (AB quartet, JAB=13.8 Hz, 2H), 2.79 (q, J=7.5 Hz, 2H),2.31-2.19 (m, 4H), 2.21 (s, 3H), 2.15 (s, 3H), 2.12-2.08 (m, 2H),1.57-1.51 (m, 1H), 1.29 (t, J=7.5 Hz, 3H).

[0484]¹³C NMR (CD₃OD) δ: 172.2, 170.8, 153.7, 153.6, 142.7, 141.9,135.0, 134.2, 67.1, 57.3, 55.5, 46.6, 34.0, 31.3, 30.3, 27.7, 22.1, 9.7,9.2, 9.1.

[0485] LRMS (EI) calcd for C₁₈H₂₀NO₁₀ (M+−C₂H₅O₃S) 410.11, found 410.19m/z.

1. A compound of the formula I

wherein R¹¹ is CO₂R¹⁴ and R¹² is hydrogen or fluoro; or R¹¹ is hydrogenor fluoro and R¹² is CO₂R¹⁴; R¹³ and R¹⁴ are, independently, hydrogen,—CHR¹⁵O₂CXR¹⁶ or a group selected from 3-phthalidyl or

X is O, N, S, or a bond; R¹⁵ is hydrogen, (1-10C) alkyl, (2-4C) alkenyl,aryl, or arylalkyl; R¹⁶ is (1-10C) alkyl, (2-4C) alkenyl, (2-4C)alkynyl, or aryl; and R¹⁷ is hydrogen, (1-10C) alkyl or phenyl; providedwhen R¹⁴ is hydrogen, R¹³ is not hydrogen; or a pharmaceuticaiiyacceptable salt tnereof.
 2. A compound of claim 1 wherein R¹¹ is CO₂R¹⁴and R¹² is hydrogen or fluoro; or R¹¹ is hydrogen or fluoro and R¹² isCO₂R¹⁴; R¹³ and R¹⁴ are, independently, hydrogen, —CHR¹⁵O₂CXR¹⁶ or agroup selected from 3-phthalidyl or

X is O, N, S, or a bond; R¹⁵ is hydrogen, (1-10C) alkyl, (2-4C) alkenyl,aryl, or arylalkyl; R¹⁶ is (1-10C) alkyl, (2-4C) alkenyl, (2-4C)alkynyl, or aryl; and R¹⁷ is (1-1° C.) alkyl.
 3. The compound (or saltthereof) of any one of claims 1 or 2 wherein (1-10C) alkyl is methyl,ethyl, n-propyl, isopropyl, t-butyl, or cyclohexyl; and aryl is phenyl,4-methoxyphenyl, naphthan-1-yl or naphthan-2-yl.
 4. The compound (orsalt thereof) of any one of claims 1 or 2 wherein R¹¹ is CO₂R¹⁴; R¹² ishydrogen; R¹³ and R¹⁴ are, independently, hydrogen, —CHR¹⁵O₂CXR¹⁶, or agroup selected from 3-phthalidyl or

R¹⁵ is hydrogen or methyl; R¹⁶ is isopropyl, 4-methoxyphenyl, phenyl,napthalen-1-yl, napthalen-2-yl, cyclohexyl, t-butyl, n-propyl, methyl,or ethyl; R¹⁷ is methyl; and X is O or a bond.
 5. The compound (or saltthereof) of any one of claims 1 or 2 wherein R¹³ and R¹⁴ are—CHR¹⁵O₂CXR¹⁶ or a group selected from 3-phthalidyl or


6. The compound (or salt thereof) of claim 5 which is selected from: a)(1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-dipivaloyloxymethyl ester hydrochloride; b)(1S,2S,5R,6S)-bis-(5-methyl-2-oxo-[1,3]dioxolen-4-ylmethyl)2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylate ethanesulfonic acid; c)(1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-di-(3′-phthalidyl) ester hydrochloride; or d)(1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2,6-dipropanoyloxymethyl ester hydrochloride.
 7. The compound (or saltthereof) of any one of claims 1 or 2 wherein R¹³ is —CHR¹⁵O₂CXR¹⁶ andR¹⁴ is hydrogen.
 8. The compound (or salt thereof) of claim[[s 1-4 or]]7 which is selected from: a)(1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2-(4′-methoxy-benzoyloxy)methyl ester hydrochloride; or c)(1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2-(naphthalene-1′-carbonyloxymethyl) ester hydrochloride.
 9. Apharmaceutically acceptable salt of a compound of formula I as claimedin any one of claims 1 or 2 which is an acid-addition salt made with anacid which provides a pharmaceutically acceptable anion or, for acompound which contains an acidic moiety, which is a salt made with abase which provides a pharmaceutically acceptable anion.
 10. Apharmaceutical formulation comprising in association with apharmaceutically acceptable carrier, dilutant or excipient, a compoundof formula I (or a pharmaceutically acceptable salt thereof) as providedin any one of claims 1 or
 2. 11. A process for preparing the compound offormula I, or a pharmaceutically acceptable salt thereof, as claimed inclaim 1 comprising: (A) for a compound of formula I in which R¹³ is anester and R¹⁴ is hydrogen, deprotecting the amine group and selectivelydeprotecting the ester group of a compound of formula II

in which R¹³ is an ester and R¹⁴ is a carboxy protecting group; (B) fora compound of formula II in which R¹³ and R¹⁴ are not hydrogen (adi-ester), esterifying a compound of formula II in which R¹³ is hydrogenand R¹⁴ is not hydrogen; (C) for a compound of formula II in which R¹³is hydrogen and R¹⁴ is not hydrogen, selectively esterifying a compoundof formula II in which R¹³ and R¹⁴ are both hydrogen (a di-acid); (D)for a compound of formula II in which R¹³ and R¹⁴ are both hydrogen (adi-acid), amidating the amine group of a compound of formula I with anamine protecting group; (E) for a compound of formula I where R¹³ ishydrogen and R¹⁴ is an ester group, deprotecting and ring-opening acompound of formula IV

(F) for a compound of formula IV in which R¹⁴ is an ester group,esterifying the acid group of a compound of formula IV in which R¹⁴ ishydrogen; (G) for a compound of formula IV in which R¹⁴ is hydrogen (anacid), protecting and cyclizing a compound of formula III; (H) for acompound of formula I in which R¹³ and R¹⁴ are not hydrogen (adi-ester), deprotecting the amine group of a compound of formula II; (I)for a compound of formula II in which R¹³ and R¹⁴ are not hydrogen (adi-ester), esterifying the carboxy groups of a compound of formula II inwhich R¹³ and R¹⁴ are both hydrogen (a di-acid); whereafter, for any ofthe above procedures, when a functional group is protected using aprotecting group, removing the protecting group; whereafter, for any ofthe above procedures, when a pharmaceutically acceptable salt of acompound of formula I is required, it is obtained by reacting the basicform of such a compound of formula I with an acid affording aphysiologically acceptable counterion, or, for a compound of formula Iwhich bears an acidic moiety, reacting the acidic form of such acompound of formula I with a base which affords a pharmaceuticallyacceptable cation, or by any other conventional procedure. 12.(Cancelled)
 13. (Cancelled)
 14. A method for treating a neurologicaldisorder in a patient which comprises administering to the patient inneed of treatment thereof a pharmaceutically-effective amount of acompound of claim
 1. 15. The method of claim 14 wherein saidneurological disorder is cerebral deficits subsequent to cardiac bypassand grafting; cerebral ischemia; spinal cord trauma; head trauma;Alzheimer's Disease; Huntington's Chorea; amyotrophic lateral sclerosis;AIDS-induced dementia; perinatal hypoxia; hypoglycemic neuronal damage;ocular damage and retinopathy; cognitive disorders; idiopathic anddrug-induced Parkinson's Disease; muscular spasms; migraine headaches;urinary incontinence; drug tolerance, withdrawal, and cessation; smokingcessation; emesis; brain edema; chronic pain; sleep disorders;convulsions; Tourette's syndrome; attention deficit disorder; andtardive dyskinesia.
 16. The method of claim 15 wherein said neurologicaldisorder is drug tolerance, withdrawal, and cessation; or smokingcessation.
 17. (Cancelled)
 18. (Cancelled)
 19. (Cancelled)
 20. A methodfor treating a psychiatric disorder in a patient which comprisesadministering to the patient in need of treatment thereof apharmaceutically-effective amount of a compound of claim
 1. 21. Themethod of claim 20 wherein said psychiatric disorder is schizophrenia,anxiety and related disorders, depression, bipolar disorders, psychosis,and obsessive compulsive disorders.
 22. The method of claim 21 whereinsaid psychiatric disorder is anxiety and related disorders. 23.(Cancelled)
 24. (Cancelled)
 25. (Cancelled)
 26. A pharmaceuticalformulation comprising the compound of claim 1 in combination with oneor more pharmaceutically-acceptable carriers, diluents, or excipients.27. (Cancelled)
 28. (Cancelled)